KR20080031390A - Benzoimidazole compound capable of inhibiting prostaglandin d synthetase - Google Patents

Abstract

A benzoimidazole compound represented by the general formula (I) or a salt thereof: (I) wherein X1 represents an oxygen atom or a carbonyl group; and R1 represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents, provided that a compound represented by the general formula (I) wherein the substituent is a phosphoric acid group or a phosphate ester group is excluded. The benzoimidazole compound or salt thereof has an excellent prostaglandin D synthetase inhibitory activity, and is useful as a prophylactic and/or therapeutic agent for a disease associated with prostaglandin D2 or a metabolite thereof, such as an allergic disease or an inflammatory disease or as an inhibitor for the exacerbation of Alzheimer disease or cerebral damage.

Description

Benzoimidazole compounds that inhibit prostaglandin D synthase {BENZOIMIDAZOLE COMPOUND CAPABLE OF INHIBITING PROSTAGLANDIN D SYNTHETASE}

The present invention provides a benzoimidazole compound or a salt thereof as an active ingredient, in particular a novel benzo useful as an agent for preventing and / or treating allergic diseases, inflammatory diseases due to prostaglandin D synthase inhibitory action, and for inhibiting exacerbation of Alzheimer's disease or brain damage It relates to a medicament comprising an imidazole compound or a salt thereof as an active ingredient.

A series of lipid mediators collectively referred to as eicosanoids, such as prostaglandins and leukotrienes, are synthesized by an arachidonic acid cascade starting with arachidonic acid cut from the phosphorus lipids of the membrane according to various stimuli. In particular, prostanoid is a kind of arachidonic acid metabolite synthesized by using prostaglandin H2 produced by cyclooxygenase as an intermediate in the arachidonic acid cascade. And thromboxane A2 are known to be synthesized.

Prostanoids act as topically active hormone-type chemotransmitters and are generally synthesized in response to local tissue damage, stimulation by hormones, bacterial peptides, antigens, and stimulation by inflammatory mediators such as cytokines. The produced prostanoids bind to specific receptors expressed on the cell surface. They express various effects in most tissues, and most inflammatory responses and immune systems in addition to the functions of in vivo function such as gastric acid secretion and blood flow. It is known to affect function.

Synthetic enzymes that produce prostaglandin D2 are called prostaglandin D synthetases and two types of hematopoietic enzymes and lipocarinic enzymes are known.

Hematopoietic enzymes in humans are mainly distributed in the placenta, lung, fetal liver, lymph nodes, brain, heart, thymus, bone marrow and spleen. And at the cellular level, microglia cells in the brain, myeloid megakaryocytes, and Langerhans cells in the skin; Cooper cells in liver; Microphage; Expression of most antigen presenting cells such as dendritic cells, mast cells and Th2 cells has been reported.

Lipocarin-type enzymes are mainly distributed in the central nervous system, heart, testis epithelium and testis of the brain or spinal cord, and prostaglandin D2 produced by lipocarin-type enzymes functions as a liquid regulator of sleep and control of the brain nervous system by arachnoid membrane. It is known that not only has a function, a harmful cognitive control function and spermatogenesis control function represented by allodynia, but the lipocarin-type enzyme itself functions as a transport protein of a fat-soluble low molecular compound.

Two types of prostaglandin D2 specific receptors are known, DP1 and DP2 (sometimes called CRTH2), and DP1 is composed of bone marrow, brain, retina, digestive organs, airway epithelial cells, vascular smooth muscle, platelets, basophils, etc. It has been reported that DP2 is expressed in tissues such as bone marrow, brain, thymus, heart, cells such as Th2 cells, eosinophils, basophils, and monocytes. Prostaglandin D2, produced locally by hematopoietic enzymes in various stimuli, binds to these receptors by inhibiting platelet aggregation, vasodilation, vascular permeability, mucin production, airway smooth muscle contraction, antigen presenting cells; Th2 cells; It is thought to be involved in the development and exacerbation of allergic diseases and inflammatory diseases, in particular, in the same manner, as in lactose and activation of eosinophils.

In allergic diseases such as bronchial asthma and allergic rhinitis, arachidonic acid cascade is activated in the mast cells activated by the combination of antigen and immunoglobulin E, which releases various inflammatory mediators and plays an important role in causing allergic symptoms. It is thought that it is accomplishing. Among them, prostaglandin D2 is the most inflammatory mediator produced and released in large quantities, and is detected in high concentrations in bronchial alveolar lavage fluid of asthmatic patients (Non-Patent Documents 1 and 2). In addition, it has been reported that airway contractions are recognized by inhalation of prostaglandin D2 in asthmatic patients (Non-Patent Document 3). In addition, high expression of hematopoietic enzymes in mast cells and inflammatory cells in submucosal or chronic sinusitis patients of allergic rhinitis patients, and DP2 expresses T cells in eosinophils infiltrated by DP1 and DP2. (Non-Patent Document 4), which has a high DP2 positive rate of skin lymphocyte homing antigen-positive cells (CLA) according to the severity of atopic dermatitis patients (Non-Patent Document 5). The onset and exacerbation of allergic diseases are derived from hematopoietic enzymes. It is thought that prostaglandin D2 which plays a role plays an important role (nonpatent literature 6-8).

Recently, allergic reactions are promoted in mice overexpressed with prostaglandin D synthetase (Non Patent Literature 9), and it has been reported that allergic reactions are not shown in knockout mice with prostaglandin D2 receptor (Non Patent Literature 10). It has also been reported that in mice with hematopoietic enzyme-deficient mice, there is a slight increase in muscle necrosis and traumatic brain injury.

Therefore, prostaglandin D2 produced by two kinds of enzymes, hematopoietic enzyme and lipocarine type enzyme, is involved in the function of onset or exacerbation of various diseases including allergic diseases, and in vivo regulatory mechanisms. Improvement is thought to be very effective as a medicine for various diseases.

For example, HQL-79 (4-benzhydryloxy-1-{3- (1H-tetrazol-5-yl) -propyl} piperidine) has been reported for hematopoietic enzyme inhibitors (ratio) Patent Documents 11 and 12). HQL-79 is a compound that combines histamine H1 antagonism and has been reported to suppress airway inflammatory conditions such as eosinophil infiltration into the airways and delayed asthmatic reactions in the asthma model, but its activity is not sufficient. . In addition, there is a disclosure regarding the provision of a prostaglandin D synthetase inhibitor (Patent Documents 8 and 9). Although the enzyme inhibitory activity exceeds HQL-79, the activity is not sufficient.

Antihistamines, chemical mediator free inhibitors, leukotriene receptor antagonists, thromboxane A2 synthesis inhibitors and receptor antagonists, Th2 cytokine inhibitors, and immunosuppressants are currently used as antiallergic agents for the purpose of preventing or treating allergic diseases. (Non-Patent Document 13). However, these anti-allergic agents are not easy to use because they have problems such as insufficient drug efficacy, central side effects such as drowsiness or sedation, digestive symptoms such as diarrhea, and side effects such as immunosuppression. . In addition, the steroid is a drug used for the treatment of most inflammatory diseases as well as allergic diseases due to its strong anti-inflammatory action, and is easy to use due to side effects such as infectious disease, bone damage or growth disorder, or rebound after discontinuation. It is not a drug.

On the other hand, inhibitors of prostaglandin D synthetase can be expected to be useful medicines for the prophylaxis and / or treatment of allergic or inflammatory diseases involving prostaglandin D2 or its metabolites produced by hematopoietic enzymes.

Conventional benzimidazole compounds have been widely studied as compounds useful in medicine and the like.

For example, Patent Document 1 (WO2004017963) describes a wide range of benzoimidazole compounds including 5-phenoxybenzoimidazole compounds as blood coagulation factor (Xa) inhibitors.

Patent Document 2 (Japanese Patent Laid-Open No. 2004-067629) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as mitochondrial function activators.

Patent document 3 (WO2003035065) describes a wide range of benzoimidazole compounds, including 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as protein kinase inhibitors.

Patent Document 4 (Japanese Patent Laid-Open No. 2001-515482) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as FBP agent inhibitors.

Patent document 5 (WO2002076454) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as pharmaceutical use patents for anti-tumor agents.

Patent Document 6 (Japanese Patent Laid-Open No. 2000-026430) describes a 5-phenoxybenzoimidazole compound, and describes a pyridyl group, a furyl group, and a thienyl group as substituents in the benzoimidazole 2-position.

Patent Document 7 (WO9965886) discloses a 5-benzoylbenzoimidazole compound as an insect and tick repellent agent, and a thiazolyl group is disclosed as a heterocycle of a substituent in the benzoimidazole 2-position.

Patent Document 1: International Patent Publication No. WO2004017963

Patent Document 2: Japanese Patent Laid-Open No. 2004-067629

Patent Document 3: International Publication No. WO2003035065

Patent Document 4: Japanese Patent Publication No. 2001-515482

Patent Document 5: International Patent Publication No. WO2002076454

Patent Document 6: Japanese Patent Application Laid-Open No. 2000-026430

Patent Document 7: International Patent Publication WO9965886

Patent Document 8: Japanese Patent Laid-Open No. 2004-2248

Patent Document 9: Japanese Patent Application Laid-Open No. 2004-51600

[Non-Patent Document 1] J. Immumol., 129, 1627-1631 (1982)

Non Patent Literature 2: N. Eng. J. Med., 315, 800-804 (1986)

Non Patent Literature 3: N. Eng. J. Med., 311, 209-213 (1984)

[Non-Patent Document 4] Prostaglandins & other Lipid Med. 73, 87-101 (2004)

Non Patent Literature 5: J. Invest. Dermatol. 119, 609-616 (2002)

Non-Patent Document 6: J. Immunol., 143, 2982-2989 (1989)

Non Patent Literature 7: J. Biol. Chem., 265, 371-375 (1990)

Non Patent Literature 8: J. Biol. Chem., 270, 3239-3246 (1995)

Non-Patent Document 9: J. Immunol., 168, 443-449 (2002)

Non Patent Literature 10: Science, 287, 2013-2017 (2000)

Non-Patent Document 11: Jpn. J. Pharmacol., 78, 1-10 (1998)

Non Patent Literature 12: Jpn. J. Pharmacol., 78, 11-22 (1998)

Non-Patent Document 13: “Clinical and Research,” 79, No. 2, pages 30–33 (February 2002)

The main task of the present invention is to provide a novel compound having a high effect of inhibiting prostaglandin D synthase, in particular hematopoietic prostaglandin D synthases, at low doses.

In addition, another object of the present invention is to provide a medicament that is effective in the prevention and treatment of prostaglandin D2 or its metabolite-mediated diseases based on prostaglandin D synthetase inhibitory activity, with low side effects and high safety. It is.

The present inventors earnestly studied compounds having a prostaglandin D synthetase inhibitory activity, and the novel benzoimidazole compounds represented by the following formula (I) or salts thereof have very good inhibitory effects on prostaglandin D synthetase. The present inventors discovered and further studied to complete the present invention.

That is, according to the present invention, a novel benzoimidazole compound represented by the following formula (I) or a salt thereof, a prostaglandin D synthetase inhibitor containing the active ingredient, a method for preventing or treating a disease involving prostaglandin D2 or a metabolite thereof, and the like This is provided.

Item 1: Formula (I)

[Formula I]

[Wherein, X ¹ represents an oxygen atom or a carbonyl group, and R ¹ represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents.

However, the compound represented by the formula (I) in which the substituent is a phosphoric acid group or a phosphate ester group is excluded.]

The benzimidazole compound or its salt represented by these.

Item 2: The benzimidazole compound or salt thereof according to Item 1, wherein X ¹ represents a carbonyl group.

Item 3: X ¹ represents an oxygen atom or a carbonyl group,

R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents,

The substituent on the pyrrole ring or furan ring may have a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a carbon number which may have a substituent is selected from (C = O) -R ² group the group consisting of, - an alkenyl group of to 6 and

R ² is a hydrogen atom, a hydroxy group, a substituent which may have an alkyl group of 1 to 6 carbon atoms good represents an alkoxy group or -NR ³ R ⁴ group having 1 to 6 carbon atoms of a good,

R <^3> and R <^4> is the same or different, and each has a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group, an amino group, and a substituent which may have a substituent A mono or di (C 1 -C 6 alkyl) amino group which may be present, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a saturated or unsaturated heterocyclic group which may have a substituent, or

R ³ and R ⁴ together with adjacent nitrogen atoms in the ring structure, in addition to the adjacent nitrogen atoms in addition to the saturation may have one or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms; The unsaturated cyclic amino group may be formed, and the cyclic amino group may have a substituent.

The benzimidazole compound according to item 1 or a salt thereof.

Item 4: X ¹ represents a carbonyl group,

R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents,

The substituent on the pyrrole ring or furan ring may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, a nitro group, a halogen atom as a substituent, a hydroxy group and a -NR ^{3 '} R ^{4 '} group. An alkenyl group having 2 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group as the alkyl group of 6 to 6 or a substituent, or-(C = O) -R ² ,

R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ³ R ⁴ group,

R ^{3 ′} and R ^{4 ′} are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or

R ^{3 ′} and R ^{4 ′} may have one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure together with the adjacent nitrogen atoms. A saturated or unsaturated cyclic amino group may be formed,

R ³ And R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other one having a hydrogen atom, a hydroxy group or a substituent having 1 to 6 carbon atoms and optionally having a substituent group having 1 to 6 carbon atoms. Mono or di (C1-C6 alkyl) amino group which may have an alkoxy group, an amino group, a substituent, a C6-C14 aryl group which may have a substituent, or the monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent Or

R ³ And R ⁴ together with the adjacent nitrogen atom form a saturated or unsaturated cyclic amino group which may have one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. The cyclic amino group may be a substituent having a halogen atom, a hydroxyl group, a cyano group, a nitro group, a formyl group, a carboxyl group, a C6-C6 alkyl group which may have a substituent, or a C6-C14 that may have a substituent. May have 1 to 3 groups selected from the group consisting of an aryl group, a (C 1 -C 6 alkoxy) carbonyl group which may have a substituent and a mono or di (C 1 -C 6 alkyl) aminocarbonyl group which may have a substituent

The benzimidazole compound according to item 1 or a salt thereof.

Item 5: X ¹ represents a carbonyl group,

R ¹ is a furan ring having ¹ to 3 substituents, or a pyrrole ring having ¹ to 3 substituents with a hydrogen atom bonded to a nitrogen atom,

The substituents bonded to the pyrrole ring and the furan ring may have a group selected from the group consisting of a halogen atom, a cyano group, a nitro group and a substituent selected from the group consisting of a halogen atom, a hydroxy group, a dimethylamino group and a pyrrolidinyl group. as the alkyl group, the substituent of 6 cyano group, a carboxyl group and (C1-C6 alkoxy group) which may have one 1 is selected from the group consisting of a carbonyl group and good ethenyl group - is selected from (C = O) -R ² group consisting of,

R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or —NR ³ R ⁴ ,

One of R ³ and R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 3 carbon atoms which may have a substituent, or having 1 to 3 carbon atoms. Selected from the group consisting of an alkoxy group, a phenyl group which may have a substituent, or a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group and a benzothiazolyl group A heterocyclic group (wherein the heterocyclic group may have a substituent), or

R ³ and R ⁴ together with adjacent nitrogen atoms may form a saturated or unsaturated cyclic amino group which may have one hetero atom selected from a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure;

The benzimidazole compound according to item 1 or a salt thereof.

Item 6: X ¹ represents a carbonyl group,

R ¹ is a furan ring having two or three substituents, or a pyrrole ring having two or three substituents in combination with a hydrogen atom bonded to a nitrogen atom, wherein the two constituents of the furan ring and the pyrrole ring The substituent on the carbon atom is an alkyl group having 1 to 6 carbon atoms, a hydrogen atom is bonded to one remaining carbon atom, or a cyano group or a — (C═O) —R ² group is bonded as a substituent.

R ² represents a hydroxy group, an alkoxy group having 1 to 3 carbon atoms, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Phenyl group, morpholino group, isoxazolyl group, indolyl group, methylenedioxy which may have 1 to 3 groups selected from the group consisting of a halogen group, a cyano group and a C1-6 alkoxy group as the alkoxy group of 3 A phenyl group, ethylenedioxyphenyl group, dihydrobenzofuranyl group, or benzothiazolyl group, or

—NR ³ R ⁴ group represents a pyrrolidinyl group, thiazolidinyl group, pyrazolinyl group, morpholino group, or piperazinyl group

The benzimidazole compound according to item 1 or a salt thereof.

Item 7: X ¹ represents a carbonyl group,

R ¹ is a furan ring having three substituents and bonded to a benzoimidazole ring at the 4-position, or having 3 substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position Represents a pyrrole ring,

In the substituents on the furan ring and the pyrrole ring, the substituents at the 3- and 5-positions are an alkyl group having 1 to 3 carbon atoms, the 2-position substituent represents a cyano group or a-(C = O) -R ² group,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Or a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group and a C1 to C3 alkoxy group as the alkoxy group of 3 or a substituent, or

-NR ³ R ⁴ group represents a pyrrolidinyl group, a pyrazolinyl group, or a morpholino group

The benzimidazole compound according to item 1 or a salt thereof.

Item 8: X ¹ represents a carbonyl group,

R ¹ represents a pyrrole ring having three substituents and a bond to a benzoimidazole ring at the 4-position together with a hydrogen atom bonded to a nitrogen atom,

Among the substituents on the pyrrole ring, the substituents at the 3- and 5-positions represent a methyl group, the 2-position substituents represent a-(C = 0) -R ² group,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other represents a C1-C3 alkyl group or a C1-C3 alkoxy group which may have a substituent, or

-NR ³ R ⁴ group represents a pyrrolidinyl group or a morpholino group

The benzimidazole compound according to item 1 or a salt thereof.

Item 9:

(4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethyl-2-furanylcarbonyl) pyrrolidine,

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid),

2- (2-cyano-3,5-dimethyl-pyrrole-4-yl) -benzoylbenzoimidazole,

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) morpholine,

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) pyrazoline, or

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide

The benzimidazole compound of Claim 1 or its salt.

Item 10: A pharmaceutical composition comprising an effective amount of at least one of the compounds according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 11: A prostaglandin D synthetase inhibitor containing an effective amount of at least one of the compounds according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 12: An agent for preventing a disease involving prostaglandin D2 or a metabolite thereof, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. And / or therapeutic agents.

Item 13: The prophylactic and / or therapeutic agent according to item 12, wherein the disease involving prostaglandin D2 or a metabolite thereof is any one of an allergic disease, an inflammatory disease, Alzheimer's disease, or brain injury.

Item 14: An agent for preventing and / or treating an allergic disease, comprising an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 15: An agent for preventing and / or treating an inflammatory disease, which comprises an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 16: An agent for preventing and / or treating Alzheimer's disease or brain injury, comprising an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Item 17: The method for preventing or treating a disease involving prostaglandin D2 or a metabolite thereof, comprising administering to the patient an effective amount of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof.

Item 18: Use of the compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof for producing a prostaglandin D synthetase inhibitor.

Effects of the Invention

According to the present invention there is provided a novel benzimidazole compound represented by formula (I) or a salt thereof, which is useful as a prostaglandin D synthetase inhibitor, in particular a hematopoietic enzyme inhibitor.

The benzimidazole compound or salt thereof of the present invention has excellent prostaglandin D synthetase inhibitory activity, for example, has a hematopoietic prostaglandin D synthetase inhibitory activity superior to HQL-79, which is conventionally known as a hematopoietic enzyme inhibitor. (See Experimental Example 1 described later).

Thus, the corresponding benzimidazole compounds of the present invention or salts thereof are based on their excellent prostaglandin D synthetase inhibitory activity, and thus preventive and / or therapeutic agents for diseases involving prostaglandin D2 or its metabolites, for example allergic or inflammatory diseases, It is useful as an inhibitor of deterioration of Alzheimer's disease and brain damage, and other useful effects can be expected.

Of the present invention Benzoimidazole  compound

The benzimidazole compound of the present invention is a compound represented by the following general formula (I).

[Formula I]

[Wherein, X ¹ represents an oxygen atom or a carbonyl group, and R ¹ represents a furan ring having a substituent or a pyrrole ring which may have a substituent. Especially R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents.

However, the compound represented by the formula (I) in which the substituent is a phosphoric acid group or a phosphate ester group is excluded.]

The benzimidazole compounds represented by the general formula (I) of the present invention are novel compounds and are compounds not specifically disclosed in the above-mentioned prior art documents.

For example, Patent Document 1 (WO2004017963) describes a wide range of benzimidazole compounds, including 5-phenoxybenzoimidazole compounds as blood coagulation factor (Xa) inhibitors. However, there is no specific disclosure of the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as substituents in the benzimidazole 2-position.

In addition, Patent Document 2 (Japanese Patent Laid-Open No. 2004-067629) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as mitochondrial function activators. However, this patent compound discloses a phenyl group, a pyridyl group, etc. as a substituent of a benzimidazole 2-position, and differs in that the compound of this invention has a pyrrole ring and a furan ring which are substituents of a benzoimidazole 2-position.

Patent document 3 (WO2003035065) describes a wide range of benzoimidazole compounds, including 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as protein kinase inhibitors. However, there is no specific disclosure of the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as substituents in the benzimidazole 2-position.

Patent Document 4 (Japanese Patent Laid-Open No. 2001-515482) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as FBP agent inhibitors. However, the patent compound differs from the compound of the present invention in that the furanyl group in the benzimidazole 2-position has a phosphoric acid group or a phosphate ester group as a substituent.

Patent document 5 (WO2002076454) describes 5-phenoxybenzoimidazole compounds and 5-benzoylbenzoimidazole compounds as pharmaceutical use patents for anti-tumor agents. However, there is no specific disclosure of the benzimidazole compound of the present invention having a pyrrole ring and a furan ring as substituents in the benzimidazole 2-position.

Patent Document 6 (Japanese Patent Laid-Open No. 2000-026430) describes a 5-phenoxybenzoimidazole compound, and claims a pyridyl group, a furyl group, and a thienyl group as a substituent in the benzoimidazole 2-position. However, the patented compound differs from the compound of the present invention having no substituent at the 6th position in that it has a substituent at the 6th position of benzoimidazole.

Patent Document 7 (International Patent Publication No. WO9965886) discloses a 5-benzoylbenzoimidazole compound as an insect repellent repellent agent, and a thiazolyl group is disclosed as a heterocycle of a benzoimidazole 2-position substituent. The compound differs in that it has a pyrrole ring and a furan ring, which are substituents of benzoimidazole 2-position.

The compound represented by general formula (I) is as follows.

In the compound of the present invention, compound (I) wherein X ¹ is a carbonyl group is preferable.

Moreover, the compound of this invention is typically

X ¹ represents an oxygen atom or a carbonyl group,

R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents,

The substituent on the furan ring or the pyrrole ring may be a halogen atom, a cyano group, a nitro group, or an alkyl group having 1 to 6 carbon atoms which may have a substituent, a cycloalkyl group having 3 to 7 carbon atoms which may have a substituent, or a carbon number which may have a substituent. is selected from (C = O) -R ² group the group consisting of, - an alkenyl group of 2 to 6 and

R ² is a hydrogen atom, a hydroxy group, a substituent which may have an alkyl group of 1 to 6 carbon atoms good represents an alkoxy group or -NR ³ R ⁴ group having 1 to 6 carbon atoms of a good,

R <^3> and R <^4> is the same or different, and each has a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group, an amino group, and a substituent which may have a substituent A mono or di (C 1 -C 6 alkyl) amino group which may be present, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a saturated or unsaturated heterocyclic group which may have a substituent, or

R ³ and R ⁴ together with adjacent nitrogen atoms in the ring structure, in addition to the adjacent nitrogen atoms in addition to the saturation may have one or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms; An unsaturated cyclic amino group may be formed and this cyclic amino group may be a benzoimidazole compound represented by general formula (I) which may have a substituent.

Especially as a compound which concerns on one Embodiment of this invention,

X ¹ represents a carbonyl group,

R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents,

The substituent on the furan ring or the pyrrole ring may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, a nitro group, a halogen atom as a substituent, a hydroxy group and a -NR ^{3 '} R ^{4 '} group. Alkenyl group having 2 to 6 carbon atoms or-(C = O) -R which may have 1 to 3 groups selected from the group consisting of 1 to 6 alkyl groups and substituents, a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group. ² ,

R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ³ R ⁴ group,

R ^{3 ′} and R ^{4 ′} are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or

R ^{3 ′} and R ^{4 ′} may have one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure together with the adjacent nitrogen atoms. A saturated or unsaturated cyclic amino group may be formed,

R <^3> and R <^4> is a hydrogen atom or a C1-C6 alkyl group, and the other C1-C6 alkyl group and substituent which may have a hydrogen atom, a hydroxyl group, and a substituent are C1-C6 Mono or di (C1-C6 alkyl) amino group which may have a 6 alkoxy group, an amino group, a substituent, C6-C14 aryl group which may have a substituent, or monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent Indicate ventilation, or

R ³ and R ⁴ together with adjacent nitrogen atoms, in addition to the adjacent nitrogen atoms in the ring structure, are saturated or unsaturated, which may have one or two complex atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. A cyclic amino group may be formed, and the cyclic amino group may have a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, a carboxy group, or a C 1-6 alkyl group which may have a substituent, or a carbon number 6 which may have a substituent as a substituent. It may have 1-3 groups selected from the group which consists of a mono- or di (C1-C6 alkyl) aminocarbonyl group which may have a -14 aryl group, a C1-C6 alkoxycarbonyl group, and a substituent.

The benzimidazole compound represented by general formula (I) is mentioned.

In the present specification, in the case of “you may have a substituent” for a structure, it means that there may be one or two or more “substituents” at chemically possible positions on the structure. In addition, in the present specification, the term "having a substituent" for a structure means having one or two or more "substituents" at a chemically possible position on the structure.

The kind of substituent which may exist (or may be present), the number of substituents, and a substitution position are not specifically limited, When two or more substituents exist, they may be same or different. Examples of the "substituent" include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms. ,-(C = O) -R ² group, -NR ³ R ⁴ group, -NR ^{3 '} R ^{4 '} group, oxo group, saturated or unsaturated heterocyclic ring, aryl group having 6 to 14 carbon atoms, etc. are exemplified. When a substituent is present, the number is typically 1-3.

As a "halogen atom", a fluorine atom, a chlorine atom, a bromine atom, an iodine atom are mentioned, for example.

"C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec- A butyl group, tert- butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, etc. are mentioned.

As a "C3-C7 cycloalkyl group", a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc. are mentioned, for example.

As "a C2-C6 alkenyl group", an ethenyl group, an allyl group, butenyl group, butadienyl group, hexatrienyl group, etc. are mentioned, for example.

"C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, iso part A oxy group, sec-butoxy group, tert- butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxy group, n-hexyloxy group, etc. are mentioned.

Examples of R ² - "(C = O) -R 2 group", for example, hydrogen atom, hydroxyl group, alkyl group having 1 to 6 carbon atoms, an alkoxy group, -NR ³ R ⁴ group, a saturated group having 1 to 6 carbon atoms Or an unsaturated heterocyclic group, a C6-C14 aryl group, etc. are mentioned.

"-NR ³ R ⁴ group" and "-NR ^{3 'R 4'} group" of ^{R 3, R 4, R 3} ' and R ^4' as, the same or different from each other, respectively, for example, a hydrogen atom, a hydroxyl Time period, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an amino group, a mono or a di (C 1 -C 6 alkyl) amino group, a (C 1 -C 6 alkoxy) carbonyl group, a mono or a di (C 1 -C 6 alkyl) aminocarbonyl group, Saturated or unsaturated heterocyclic group, a C6-C14 aryl group, etc. are mentioned.

In addition, the "-NR ³ R ⁴ group" and the "-NR ^{3 '} R ^{4 '} group" each represent a saturated or unsaturated cyclic amino group (especially, in addition to the adjacent nitrogen atom, in addition to the adjacent nitrogen atom, nitrogen atom, oxygen atom and A 5- or 6-membered saturated or unsaturated cyclic amino group which may have one or two complex atoms selected from the group consisting of sulfur atoms) may be formed, for example, azetidinyl group, pyrrolidinyl group, pipepe Lidinyl group, piperazinyl group, morpholino group, thiomorpholino group, homopiperidinyl group, imidazolyl group, pyrrolyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group , Imidazolinyl group, pyrazolinyl group, pyrazolyl group, triazolyl group and the like.

Examples of the “saturated or unsaturated heterocycle” include pyrrolidinyl group, piperidinyl group, piperadinyl group, morpholino group, thiomorpholino group, homopiperidinyl group, imidazolyl group, thienyl group, furyl group, Pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyridyl group, pyrimidinyl group, pyridyl group, indolyl group, Isoindolyl group, indazolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, benzofuranyl group, dihydrobenzofuranyl group, benzoimidazolyl group, benzoxazole group, benzothiazolyl group, furinyl group, quinolyl group , Isoquinolyl group, quinazolyl group, quinoxalyl group, 2, 3, 4, 5-tetrahydro-3-oxo-pyridazine-6-yl group and the like.

As a "C6-C14 aryl group", a phenyl group, a naphthyl group, an anthracene group, etc. are mentioned, for example.

“Mono or di (C 1 -C 6 alkyl) amino group” refers to an amino group having 1 to 6 carbon atoms, a linear or branched alkyl group as one or two substituents, for example, methylamino group, ethylamino group, n-propylamino group. , n-hexylamino group, dimethylamino group, methylethylamino group, ethyl isobutylamino group and the like.

As "(C1-C6 alkyl) carbonyl group", an acetyl group, a propionyl group, butyroyl group etc. are mentioned, for example.

As "(C1-C6 alkoxy) carbonyl group", for example, a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert -Butoxycarbonyl group, n-pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, n-hexyloxycarbonyl group, etc. are mentioned.

As "mono or di (C1-C6 alkyl) aminocarbonyl group", for example, methylaminocarbonyl group, ethylaminocarbonyl group, n-propylaminocarbonyl group, isopropylaminocarbonyl group, n-butylaminocarbonyl group, isobutylaminocarbonyl group, sec- Butylaminocarbonyl group, tert-butylaminocarbonyl group, n-pentylaminocarbonyl group, isopentylaminocarbonyl group, neopentylaminocarbonyl group, n-hexylaminocarbonyl group, dimethylaminocarbonyl group, methylethylaminocarbonyl group, ethyl isobutylaminocarbonyl group, etc. are mentioned. have.

As a substituent which the substituent or pyrrole ring which the furan ring represented by R <^1> in Formula (I) may have, the said substituent is illustrated, Preferably it is a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group, carbon number A cycloalkyl group having 3 to 7, an alkenyl group having 2 to 6 carbon atoms, or a-(C = O) -R ² group [the alkyl group, the cycloalkyl group and the alkenyl group may further have the above substituents], and more preferably. Preferably a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, or a-(C = O) -R ² group, wherein the alkyl group is a halogen atom, a hydroxyl group and a NR ^{3 'R 4'} may have a substituent selected from the group, the alkenyl group is a cyano group, a carboxyl group and (C1-C6 alkoxy group) which may have a substituent selected from the group well], represented by R ¹ The substituent having a roll good which may have ring, or a furan ring, and particularly preferably a cyano group, an alkyl group having 1 to 6 carbon atoms, or - a (C = O) -R ² group.

As a "halogen atom" which is a substituent which the substituent or pyrrole ring which the furan ring represented by R <^1> represents in Formula (I) may have, the said halogen atom is illustrated, Preferably it is a fluorine atom, a chlorine atom, or a bromine atom, The number of halogen atoms is typically one.

As the "alkyl group of 1 to 6 carbon atoms" of "the alkyl group of 1 to 6 carbon atoms which may have a substituent" which is a substituent which the substituent or pyrrole ring which the furan ring represented by R <^1> shows in General formula (I) may have, said alkyl group is It is illustrated, Preferably it is a C1-C3 alkyl group, More preferably, it is a methyl group or an ethyl group. Moreover, as a substituent of "the C1-C6 alkyl group which may have a substituent", said substituent is illustrated, Preferably it is a halogen atom, a hydroxyl group, a di (C1-C6 alkyl) amino group, or a saturated or unsaturated heterocyclic ring. More preferably, it is a 5- or 6-membered heterocycle which has one nitrogen atom, such as a di (C1-C6 alkyl) amino group and a pyrrolidinyl group, in a ring structure as a hetero atom, and the number of the said substituents is typically Is one.

Formula (Ⅰ) of R may have a furan ring or a pyrrole ring having substituent represented by ^one of substituents as the "cycloalkyl group of 3 to 7 carbon atoms" in "optionally having a substituent, a cycloalkyl group of 3 to 7 carbon atoms good", in the Cycloalkyl groups are exemplified and are preferably cyclopentyl groups or cyclohexyl groups. Moreover, as a substituent of "the C3-C7 cycloalkyl group which may have a substituent", said substituent is illustrated and the number of the said substituent is typically one.

As an "alkenyl group of 2 to 6 carbon atoms" of "the alkenyl group of 2 to 6 carbon atoms which may have a substituent" which is a substituent which a substituent or a pyrrole ring which the furan ring has in Formula (I) may have, the said alkenyl group is illustrated. And preferably an ethenyl group. Moreover, as a substituent of "the C2-C6 alkenyl group which may have a substituent", the said substituent is illustrated, Preferably 1-3 are chosen from the group which consists of a cyano group, a carboxy group, and a (C1-C6 alkoxy) carbonyl group. Group is mentioned, More preferably, it is a cyano group and the number of the said substituents is typically one.

As the "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" represented by R ² in the formula (I), the above alkyl group is exemplified, and preferably an alkyl group having 1 to 3 carbon atoms. More preferably, it is a methyl group or an ethyl group. Moreover, as a substituent of "the C1-C6 alkyl group which may have a substituent", said substituent is illustrated and the number of the said substituent is typically one.

As the "carbon alkoxy group having 1 to 6 carbon atoms" of "the C1-C6 alkoxy group which may have a substituent" represented by R ² in formula (I), said alkoxy group is illustrated, Preferably it is C1-C3 An alkoxy group, more preferably a methoxy group or an ethoxy group, and particularly preferably an ethoxy group. Moreover, as a substituent of the "carbohydrate having 1-6 substituents which may have a substituent", said substituent is illustrated and the number of the said substituents is typically one.

As the "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms" represented by R3 'and R4' in the formula (I), the above alkyl group is exemplified, and preferably an alkyl group having 1 to 3 carbon atoms, More preferably, it is a methyl group.

It may have one or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the nitrogen atoms adjacent in the ring structure represented by the group —NR ^{3 '} R ^{4 ' in the} formula (I). As a saturated or unsaturated cyclic amino group ", for example, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholino group, a thiomorpholino group, a homopiperidinyl group, an imidazolyl group, a pyrrolyl group Hexamethyleneimino group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group, imidazolinyl group, pyrazolinyl group, imidazolyl group, pyrazolyl group, triazolyl group and the like. These are mentioned, Preferably it is a pyrrolidinyl group.

As the "alkyl group having 1 to 6 carbon atoms" of the "alkyl group having 1 to 6 carbon atoms which may have a substituent" represented by R ³ and R ⁴ in the formula (I), the above alkyl group is exemplified, and preferably 1 to It is an alkyl group of 3, More preferably, it is a methyl group, an ethyl group, or n-propyl group. Moreover, as a substituent of this "the C1-C6 alkyl group which may have a substituent", said substituent is illustrated, Preferably a C3-C7 cycloalkyl group, a C1-C6 alkoxy group, di (C1-C6) Alkyl) amino groups, (C1-C6 alkyl) carbonylamino groups, (C1-C6 alkoxy) carbonyl groups, carboxyl groups, saturated or unsaturated heterocycles (especially saturated or unsaturated five-membered groups having one or two nitrogen atoms in the ring structure) Or a 6-membered heterocyclic group, wherein the heterocyclic group may have one oxo group), and one or two substituents selected from the group consisting of a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and a methylenedioxy group as substituents; It is a phenyl group which has, More preferably, a methoxy group, a dimethylamino group, an acetamide group, a methoxycarbonyl group, an ethoxycarbonyl group, a carboxy group, a pyrrolidinyl group, a piperidinyl group, a pyridyl , Methylenedioxy group, a dichlorophenyl group, dimethoxy phenyl group, or 2,3,4,5-tetrahydro-3-oxo-pyridazin-6-a group, the number of these substituents is typically 1 dog.

As said "C1-C6 alkoxy group" of "the C1-C6 alkoxy group which may have a substituent" represented by R <^3> and R <^4> in general formula (I), said alkoxy group is illustrated, Preferably it is carbon number It is an alkoxy group of 1-3. As a substituent of "the C1-C6 alkoxy group which may have a substituent", said substituent is illustrated and the number is typically one.

As the "mono or di (C1-C6 alkyl) amino group" of "mono or di (C1-C6 alkyl) amino group which may have a substituent" represented by R ³ and R ⁴ in the formula (I), the mono or di (C1-C6 alkyl) amino group is illustrated. Moreover, as a substituent of the "mono or di (C1-C6 alkyl) amino group which may have a substituent", said substituent is illustrated and the number is typically one.

As the "aryl group having 6 to 14 carbon atoms" of the "aryl group having 6 to 14 carbon atoms which may have a substituent" represented by R ³ and R ⁴ in the formula (I), the above aryl group is exemplified, and preferably a phenyl group to be. As a substituent of "the C6-C14 aryl group which may have a substituent", said substituent is illustrated, Preferably it is a halogen atom, a cyano group, or a C1-C6 alkoxy group, More preferably, a cyano group The number is typically 1-3, in particular 1.

As the "saturated or unsaturated heterocycle" of "saturated or unsaturated heterocycle which may have a substituent" represented by R ³ and R ⁴ in the formula (I), the above saturated or unsaturated heterocycle is exemplified, preferably monocyclic Or a bicyclic saturated or unsaturated heterocyclic ring, more preferably a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group, or a benzothiazolyl group. Moreover, as a substituent of the "saturation or unsaturated heterocycle which may have a substituent", said substituent is illustrated and the number is 1-3 typically.

One or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure together with the adjacent nitrogen atoms represented by the —NR ³ R ⁴ group in formula (I) As a saturated or unsaturated cyclic amino group which may have, "for example, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholino group, a thiomorpholino group, a homopiperidinyl group, a pyrrolidi Nyl group, imidazolyl group, pyrrolyl group, hexamethyleneimino group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, pyrazolidinyl group, imidazolinyl group, pyrazolinyl group, imidazolyl group, Pyrazolyl group, a triazolyl group, etc. are mentioned, Preferably a nitrogen atom, an oxygen atom, and a sulfur atom are added to the nitrogen atom adjacent to a ring structure with an adjacent nitrogen atom. Ru is a 5 or 6 membered saturated or unsaturated cyclic amino group which may have one hetero atom selected from the group, More preferably, a pyrrolidinyl group, a thiazolidinyl group, a pyrazolinyl group, a morpholino group, and a pyro It is a ferrazinyl group, a piperidinyl group, More preferably, they are a pyrrolidinyl group, a pyrazolinyl group, or a morpholino group, Especially preferably, they are a pyrrolidinyl group or a morpholino group.

One or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure together with the adjacent nitrogen atoms represented by the —NR ³ R ⁴ group in formula (I) As a substituent which the saturated or unsaturated cyclic amino group which may have "may be mentioned, the said substituent is illustrated, Preferably it is a (a) halogen atom, (b) hydroxyl group, (c) cyano group, (d) nitro Group, (e) formyl group, (f) carboxyl group, (g) alkyl group having 1 to 6 carbon atoms, (h) aryl group having 6 to 14 carbon atoms, (i) (C1-C6 alkoxy) carbonyl group, or (j) mono Or a di (C 1 -C 6 alkyl) aminocarbonyl group, a corresponding alkyl group (g), a corresponding aryl group (h), a corresponding (C 1 -C 6 alkoxy) carbonyl group (i), and a corresponding mono or di (C 1 -C 6 alkyl) aminocarbonyl group ( j) may further have said substituent. The number of substituents (particularly the substituents of (a) to (j) above) which the saturated or unsaturated heterocycle may have is 1 to 2, in particular 1.

As said "halogen atom" of said (a), the said halogen atom is illustrated.

The alkyl group described above is exemplified as the "alkyl group having 1 to 6 carbon atoms" in the above-mentioned (g) "alkyl group having 1 to 6 carbon atoms". As a substituent of "the C1-C6 alkyl group which may have a substituent", said substituent is illustrated and the number is 1-3 typically.

As an "aryl group" of the "(C6-C14 aryl group) which may have a substituent" of said (h), the said aryl group is illustrated, Preferably it is a phenyl group. As a substituent of "the C6-C14 aryl group which may have a substituent", said substituent is illustrated and the number is 1-3 typically.

As said "C1-C6 alkoxycarbonyl group" of the "(C1-C6 alkoxy) carbonyl group" which may have a substituent, said alkoxycarbonyl group is illustrated, Preferably it is an ethoxycarbonyl group. As a substituent of "(C1-C6 alkoxy) carbonyl group which may have a substituent", the said substituent is illustrated and the number is 1-3 typically.

As said "mono or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent", the said mono or di (C1-C6 alkyl) aminocarbonyl group is illustrated. As a substituent of the "mono or di (C1-C6 alkyl) aminocarbonyl group which may have a substituent", the said substituent is illustrated, Preferably it is a di (C1-C6 alkyl) amino group, a C1-C6 alkoxy group, or It is a C3-C7 cycloalkyl group, More preferably, it is a dimethylamino group, a methoxy group, or a cyclohexyl group, and the number is typically one.

Among the compounds represented by the general formula (I) of the present invention, the following compounds are more preferable.

(A) in the formula (I),

X ¹ represents a carbonyl group,

R ¹ is a furan ring having 2 or 3 substituents, or a pyrrole ring having 2 or 3 substituents together with a hydrogen atom bonded to a nitrogen atom, wherein the 2 carbon atoms constituting the furan ring and the pyrrole ring The substituent on the phase is an alkyl group having 1 to 6 carbon atoms, a hydrogen atom is bonded to one remaining carbon atom, or a cyano group or a-(C = 0) -R ² group is bonded as a substituent.

R ² represents a hydroxy group, an alkoxy group having 1 to 3 carbon atoms, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Phenyl group, morpholino group, isoxazolyl group, indolyl group, methylenedioxy which may have 1 to 3 groups selected from the group consisting of 3 alkoxy groups and a halogen atom, a cyano group and a C1-6 alkoxy group as a substituent A phenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group or a benzothiazolyl group, or

A benzoimidazole compound or a salt thereof, wherein the —NR ³ R ⁴ group represents a pyrrolidinyl group, a thiazolidinyl group, a pyrazolinyl group, a morpholino group, or a piperazinyl group.

(B) in the formula (I),

X ¹ represents a carbonyl group,

R ¹ is a furan ring having three substituents and bonded to a benzoimidazole ring at the 4-position, or having 3 substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position Represents a pyrrole ring,

Among the substituents on the furan ring and the pyrrole ring, the substituents at the 3- and 5-positions are an alkyl group having 1 to 3 carbon atoms, the 2-position substituent is a cyano group or a — (C═O) —R ² group,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Or a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group and a C1 to C3 alkoxy group as the alkoxy group of 3 or a substituent, or

Benzoimidazole compound or its salt which -NR <^3> R <^4> group represents a pyrrolidinyl group, a pyrazolinyl group, or a morpholino group.

(C) in the formula (I),

X ¹ represents a carbonyl group,

R ¹ represents a pyrrole ring having three substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position;

Among the substituents on the pyrrole ring, the substituents at the 3- and 5-positions represent a methyl group, and the 2-position substituents represent a-(C = 0) -R ² group,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

One of R ³ and R ^{4 represents} a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other represents a C 1 to 3 alkyl group or a C 1 to 3 alkoxy group which may have a substituent, or

A benzoimidazole compound or a salt thereof, wherein -NR ³ R ⁴ group represents a pyrrolidinyl group or a morpholino group.

In said (A)-(C), as a substituent of "the C1-C3 alkyl group which may have a substituent", a C1-C6 alkoxy group, di (C1-C6 alkyl) amino group, acetamide group, ( C 1 -C 6 alkoxy) carbonyl group, carboxyl group, saturated or unsaturated heterocyclic group [Preferably a saturated or unsaturated five or six membered heterocycle having one or two nitrogen atoms in the ring structure (the heterocycle is an oxo group. More preferably), more preferably a pyrrolidinyl group, a piperidinyl group, a pyridyl group, 2,3,4,5-tetrahydro-3-oxo-pyridazine-6-yl group], and 3 to 7 carbon atoms. The cycloalkyl group or the phenyl group which has one or two of a halogen atom and a C1-C6 alkoxy group as a substituent can be illustrated, The number is one.

Moreover, in said (A)-(B), as a substituent of "the C1-C3 alkoxy group which may have a substituent", said substituent is illustrated and the number is typically one.

Among the compounds of the above (A) to (C), the following compounds of the following (A ') to (C') can be mentioned.

(A ') in the formula (I),

X ¹ represents a carbonyl group,

R ¹ is a furan ring having 2 or 3 substituents, or a pyrrole ring having 2 or 3 substituents together with a hydrogen atom bonded to a nitrogen atom, wherein the 2 carbon atoms constituting the furan ring and the pyrrole ring The substituent on the phase is an alkyl group having 1 to 6 carbon atoms, a hydrogen atom is bonded to one remaining carbon atom, or a cyano group or a-(C = 0) -R ² group is bonded as a substituent.

R ² represents a hydroxy group, an alkoxy group having 1 to 3 carbon atoms, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, and a substituent (The substituent of this alkyl group is C1-C3. 6- or 6-membered saturated or unsaturated 5- or 6-membered groups having one or two nitrogen atoms in the alkoxy group, di (C1-C6 alkyl) amino group, acetamide group, (C1-C6 alkoxy) carbonyl group, carboxy group, ring structure Heterocycle (the heterocycle may have one oxo group), a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group having one or two of a halogen atom and an alkoxy group having 1 to 6 carbon atoms as a substituent; A phenyl group, morpholino group, isoxazolyl group, indolyl, which may have 1 to 3 groups selected from the group consisting of 1 to 3 alkoxy groups and a halogen atom, a cyano group and a C 1 to C 6 alkoxy group as a substituent , Methylenedioxy group, ethylenedioxy group, a dihydrobenzofuranyl group, or represents a group or benzothiazolyl, or,

Benzoimidazole compound or its salt which -NR <^3> R <^4> group shows a pyrrolidinyl group, a thiazolidinyl group, a pyrazolinyl group, a morpholino group, or a piperazinyl group.

(B ') in the formula (I),

X ¹ represents a carbonyl group,

R ¹ is a furan ring having three substituents and bonded to a benzoimidazole ring at the 4-position, or having 3 substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position Represents a pyrrole ring,

Among the substituents on the furan ring and the pyrrole ring, the 3- and 5-position substituents are alkyl groups having 1 to 3 carbon atoms, the 2-position substituents are cyano groups or — (C═O) —R ² groups,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, and a substituent (The substituent of this alkyl group is C1-C3. 6 alkoxy group, di (C1-C6 alkyl) amino group, acetamide group, (C1-C6 alkoxy) carbonyl group, carboxyl group, pyrrolidinyl group, piperidinyl group, pyridyl group, 2,3,4,5-tetra A phenyl group having one or two of a halogen atom and an alkoxy group having 1 to 6 carbon atoms as a hydro-3-oxo-pyridazine-6-yl group, a cycloalkyl group having 3 to 7 carbon atoms or a substituent), and having 1 to 3 carbon atoms Or a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group and a C1-3 alkoxy group as the alkoxy group or substituent of

Benzoimidazole compound or its salt which -NR <^3> R <^4> group represents a pyrrolidinyl group, a pyrazolinyl group, or a morpholino group.

(C ′) in the formula (I),

X ¹ represents a carbonyl group,

R ¹ represents a pyrrole ring having three substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position;

Among the substituents on the pyrrole ring, the substituents at the 3- and 5-positions represent a methyl group, and the 2-position substituents represent a-(C = 0) -R ² group,

R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group,

One of R ³ and R ⁴ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the other may have a substituent having 1 to 3 carbon atoms (the substituent of the alkyl group is an alkoxy group having 1 to 6 carbon atoms, di (C1) -C6 alkyl) amino group, acetamide group, (C1-C6 alkoxy) carbonyl group, carboxyl group, pyrrolidinyl group, piperidinyl group, pyridyl group, 2,3,4,5-tetrahydro-3 -oxo-pyridazine- 6-yl group, a cycloalkyl group having 3 to 7 carbon atoms or a substituent, or a phenyl group having one or two of a halogen atom and an alkoxy group having 1 to 6 carbon atoms), or an alkoxy group having 1 to 3 carbon atoms, or

A benzoimidazole compound or a salt thereof, wherein -NR ³ R ⁴ group represents a pyrrolidinyl group or a morpholino group.

(D) Among the compounds represented by the general formula (I), the following specific compounds are particularly mentioned. In addition, the number in parentheses after the following compound name has shown the number of the compound obtained by the Example mentioned later.

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylfuran-2-carboxamide (2),

(4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethyl-2-furanylcarbonyl) pyrrolidine (3),

N- (3,4-methylenedioxyphenyl) methyl-4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylfuran-2-carboxamide (4),

2- (2-formyl-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole (8),

2- (2-acrylonitrile-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole (9),

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid (10),

N-methyl-N- (2-dimethylaminoethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (11),

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (12),

2- (2-cyano-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole (13),

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (14),

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (15),

N- (3-methoxypropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (16),

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (17),

N- (2-acetamideethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (18),

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (19),

N- (1-methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (20),

N- (2-carboxyethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (21),

N- (1-carboxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (22),

N- (2-pyrrolidin-1-yl-ethyl) -4 (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (23),

N- (2-piperidin-1-yl-ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (24),

N- (cyclohexylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (25),

N- (5-methylisoxazol-3-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (26),

N- (4-cyanophenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (27),

N- (indol-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-carboxamide (28),

N- (3,4-methylenedioxyphenyl-1-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (29),

N- (2,3-dihydrobenzofuran-5-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (30),

N- (benzothiazol-6-yl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (31),

N- (3,4-ethylenedioxyphenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (32),

N- (2-pyridylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (33),

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (34),

N- (3,4-dichlorobenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (35),

N- (3,4-dimethoxybenzyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (36),

N- (3,4-methylenedioxyphenylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (37),

N- (2,3,4,5-tetrahydro-3-oxo-pyridazine-6-yl-methyl) -4 (5-benzylbenzoimidazol-2-yl) -3,5-dimethylpyrrole -2-carboxamide (38),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) pyrrolidine (39),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) morpholine (40),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4-phenylpiperazine (41),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) pyrazoline (42),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4-hydroxypiperidine (43),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4-ethoxycarbonylpiperidine (44),

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxylic acid (45),

N-dimethylaminoethyl-1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide ( 46),

N-methyl-N- (2-dimethylaminoethyl) -1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperi Din-4-carboxamide (47),

N- (3-dimethylaminopropyl) -1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (48),

N- (3-methoxypropyl) -1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (49),

N-cyclohexylmethyl-1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide ( 50),

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (64),

(N-hydroxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (65),

(N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (66),

(N-hydroxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (67),

4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (68),

4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid (69),

((4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -2-carbonyl) pyrrolidine (70),

((4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -2-carbonyl) morpholine (71),

N- (2- (2-pyridyl) ethyl) -4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (72),

N- (methoxy) -4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (73),

(N-methoxy-N-methyl) -4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (74),

2- (2-cyano-3,5-dimethylpyrrole-4-yl) -5-phenoxybenzoimidazole (75),

4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylfuran-2-carboxamide (76),

Or salts thereof.

(E) Among the compounds represented by the formula (I), the following compounds are particularly preferable.

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethyl-2-furanylcarbonyl) pyrrolidine,

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid,

2- (2-cyano-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole,

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

(N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) morpholine,

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) pyrazoline,

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide,

Or their salts.

In the compound (I) of the present invention, tautomers derived from benzoimidazole rings, optical isomers derived from asymmetric carbons and other isomers may be present when asymmetric carbons are present, but the present invention separates these isomers. It includes one or a mixture of both.

The compound (I) of the present invention also includes a pharmacologically acceptable prodrug. Pharmacologically acceptable prodrugs can be converted into functional groups such as amino, hydroxyl, carboxyl, and carbonyl groups of the compound (I) which is an active ingredient of the medicament of the present invention under chemical or physiological conditions such as solvolysis. It is a compound which has a functional group. As a typical functional group which forms a prodrug, the group described in "Development of a pharmaceutical" (Hirokawa Bookstore, 1990), Vol. 7, 163-198, etc. are mentioned.

In addition, the compound (I) of the present invention may form a salt with an acid addition salt or a base, and such salts, particularly pharmaceutically acceptable salts, are also included in the present invention. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, Acid addition salts with organic acids such as methanesulfonic acid, paratoluenesulfonic acid and glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, organic bases such as methylamine, ethylamine, meglumine and ethanolamine or Salts and basic ammonium salts with basic amino acids such as lysine, arginine and ornithine.

The present invention also includes various hydrates, solvates, and crystal polymorphs of the compound (I) and salts thereof of the present invention.

Preparation of the Compound of the Invention

The compound represented by general formula (I) can be manufactured by the method shown below, for example.

[ Method 1 ]

In said reaction process formula 1, R <^5> represents said R <^1> and X <^2> represents said X <^1> (it is the same below).

This production method is a method for producing a compound represented by the formula (I) by cyclizing a diaminobenzene derivative represented by the formula (1a) or a salt thereof and an aldehyde derivative represented by the formula (1b) by a conventional method.

The reaction is 0.5 to 10 mol, preferably 0.8 to 2 mol of the aldehyde derivative represented by the formula (1b) with respect to 1 mol of the diaminobenzene derivative represented by the formula (1a), preferably 0.5 to 10 mol, preferably Is usually in the presence of 0.8 to 3 moles of sodium hydrogen sulfite, potassium ferricyanide, iron chloride-oxygen and the like, esters such as ethyl acetate and butyl acetate, alcohols such as water, methanol, ethanol and isopropanol, and N and N-dimethylform It can carry out at 0 degreeC-180 degreeC, Preferably it is 50 degreeC-150 degreeC in solvent inert to reaction, such as an amide, N, N- dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, a pyridine.

The reaction is carried out in the presence of 0.5 to 10 moles, preferably 1 to 5 moles of formic acid, organic acids such as acetic acid, mineral acids such as hydrochloric acid and sulfuric acid, with respect to 1 mole of the diaminobenzene derivative represented by the formula (1a). And in solvents such as nitrobenzene and polyphosphoric acid, it may be carried out at 0 ° C to 200 ° C, preferably 50 ° C to 180 ° C.

The diamino benzene derivative represented by said Formula (1a) is well-known or can be manufactured according to a well-known method. In addition, the aldehyde derivative represented by said Formula (1b) is known or can be manufactured by a well-known method.

[ Method 2 ]

This production method amidates the diamino benzene derivative represented by the formula (1a) or its salt, and the carboxylic acid derivative represented by the formula (2b) or its reactive derivative by a conventional method, and acylaminobenzene represented by the formula (1d). It is a method provided with the 1st process of obtaining a derivative | guide_body, and the 2nd process of manufacturing the compound represented by general formula (I) by using the acylaminobenzene derivative represented by this formula (1d) for dehydration reaction.

<1st process>

In the first step, examples of the reactive derivative of the compound (2b) include acid halides such as alkyl esters having 1 to 6 carbon atoms, such as methyl esters, ethyl esters and tert-butyl esters, acid chlorides and acid bromide, and acid azide. And mixed acid anhydrides with active esters with N-hydroxybenzotriazole, N-hydroxysuccinimide, p-nitrophenol and the like, symmetric acid anhydride, alkylcarboxylic acid, p-toluenesulfonic acid and the like.

In addition, when reacting compound (2b) with free acid or without reacting an active ester or an acid halide, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphospho Lylazide, 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride, 4-chloride (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmol It is most suitable to use condensing agents such as porinium.

The reaction is carried out using the carboxylic acid derivative represented by the formula (2b) or a reactive derivative thereof represented by 0.5 to 10 mol, preferably 0.8 to 2 mol, with respect to 1 mol of the diaminobenzene derivative represented by the formula (1a), and the condensing agent Is used, the amount is 0.5 to 20 moles, preferably 0.8 to 3 moles, per 1 mole of the diaminobenzene derivative represented by formula (1a), and is usually different depending on the reactive derivative and the condensing agent used. Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, esters such as ethyl acetate, methanol, Alcohols such as ethanol, n-propanol, isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, In an inert solvent to the reaction, such as naphthyridine -20 ℃ ~150 ℃, preferably can be carried out at 0 ℃ ~100 ℃.

0.5-20 mol, preferably 0.8-5 mol of triethylamine, diisopropylethylamine, N-methylmorpholine, N, N with respect to 1 mol of diaminobenzene derivatives represented by Formula (1a) at the time of reaction. The reaction may proceed smoothly by carrying out the reaction in the presence of a base such as -dimethylaniline, N, N-diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, or lutidine.

<Second process>

The dehydration reaction of the second step is carried out at -20 ° C to 200 ° C, preferably 20 using a catalytic amount to a solvent amount of acid in an organic solvent or in the absence of a solvent inert to reactions of halogenated hydrocarbons, aromatic hydrocarbons, ethers and the like. It can be carried out at 180 ℃ to 180 ℃. Examples of the acid used may include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.

In addition, the carboxylic acid derivative represented by said Formula (2b) is well-known, or can be manufactured by a well-known method.

[ Method 3 ]

This production method amidates the aminonitrobenzene derivative represented by the formula (2a) or its salt, and the carboxylic acid derivative represented by the formula (2b) or its reactive derivative by a conventional method, and acylaminonitro represented by the formula (1c). The 1st process which makes a benzene derivative, the 2nd process which makes acylaminonitrobenzene derivative represented by obtained formula (1c) to an acylaminobenzene derivative (1d) by reduction reaction, and is represented by General formula (I) by dehydration reaction It is a method provided with the 3rd process of manufacturing a compound.

The amidation reaction of a 1st process can be performed according to the 1st process of the method 2.

As long as the reduction reaction of a 2nd process is a reaction which reduces a nitro group and converts into an amino group, either reaction conditions can be used, but it is necessary to select reaction conditions in consideration of the property of functional groups other than an acylamino nitrobenzene derivative (1c). Preferably, to 1 mole of acylaminonitrobenzene derivatives represented by formula (1c) in alcohols such as water, methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, or a mixed solvent thereof. 1 to 30 moles, preferably 3 to 10 moles of ammonium salts such as ammonium chloride salts, hydrazine hydrate, etc. in the presence of 0.01 to 5 moles, preferably 0.05 to 1 moles of reducing iron, tin chloride, iron chloride Method in which the metal is operated at 0 ° C to 150 ° C, preferably 20 ° C to 120 ° C, esters such as alcohols, ethers, ethyl acetate and butyl acetate, organic acids such as formic acid and acetic acid, or a mixed solvent thereof With respect to 1 mol of acylaminonitrobenzene derivatives represented by 1c), 0.001 to 1 mol, preferably 0.01 to 0.3 mol of carbon carrier palladium, platinum oxide, Raney nickel or the like And a method of using hydrogen gas at atmospheric pressure or pressure at 0 ° C. to 120 ° C., preferably at 20 ° C. to 100 ° C., or using formic acid, ammonium formate, cyclohexene, or the like as a hydrogen source. .

Dehydration reaction of a 3rd process can be performed according to the 2nd process of the method 2.

In addition, the aminonitrobenzene derivative represented by the formula (2a) or a salt thereof is known or can be prepared according to a known method.

[ Method 4 ]

What has a functional group of any kind of the compound of this invention can also be converted into another compound of this invention by chemically modifying the functional group, as shown in following Reaction Process Formula 4.

In the reaction process formula 4, Y ¹ may be an oxygen atom or a nitrogen atom, and R ⁶ may be any protecting group of carboxylic acid, but for example, an alkyl group having 1 to 6 carbon atoms, and NR ⁷ R ⁸ is NR ³ R described above. ⁴ and X <^2> represent said X <^1> (it is the same below).

In the derivative which has a (C1-C6 alkoxy) carbonyl group represented by Formula (I-1a, I-1b) (it can be manufactured by the method in any one of said reaction process formulas 1-3), an ester group is deprotected. Thus, the carboxylic acid derivative represented by the formula (I-2a, I-2b) can be used, and then condensed by the conventional method with the amine compound represented by the formula (5) to induce the amide derivative (I-3a, I-3b). have.

Namely, in the first step, the conversion of the derivative represented by the formula (I-1a, I-1b) to the carboxylic acid derivative represented by the formula (I-2a, I-2b) by deprotection of the ester group is R ^6. Although it also varies depending on the type of, for example, in the case of alkyl groups having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group, etc., 1 mole of ester group of the derivative represented by (I-1a, I-1b) in a suitable solvent 0.5-10 mol, Preferably it is 1-5 mol, It can obtain by making it react at -20 degreeC to 150 degreeC, Preferably it is 0 degreeC to 100 degreeC in presence of bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide. The suitable solvent is not particularly limited as long as it does not affect the reaction. For example, water, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, N, N- Dimethyl formamide, N, N- dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, etc. are mentioned, These can be used individually or in mixture.

In the second step, the amine derivative represented by the formula (5) or a salt thereof, and the carboxylic acid derivative represented by the formula (I-2a, I-2b) or a reactive derivative thereof are condensed by a conventional method to obtain a general formula (I-). The amide compound represented by 3a, I-3b) can be obtained.

Examples of the reactive derivatives of the compounds (I-2a and I-2b) include acid halides such as acid chloride and acid bromide, acid azide, N-hydroxybenzotriazole, N-hydroxysuccinimide, p-nitrophenol and the like. And mixed acid anhydrides with active esters, symmetric acid anhydrides, alkylcarboxylic acids, p-toluenesulfonic acids, and the like.

Dicyclohexylcarbodiimide or carbo when the carboxylic acid derivative represented by the formula (I-2a, I-2b) or the reactive derivative thereof is reacted with free acid, or when the active ester or acid halide is reacted without isolation. Nyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl azide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, chloride 4- (4,6-dimethoxy-1,3 It is most suitable to use a condensing agent such as, 5-triazine-2-yl) -4-methylmorpholinium.

The reaction is 0.5 to 10 moles, preferably 0.8 to 5 moles of the amine derivative represented by formula (5) or a salt thereof relative to 1 mole of the carboxylic acid derivative represented by the formulas (I-2a, I-2b) or its reactive derivative. When using a condensing agent, the amount of the condensing agent is 0.5 to 20 mol, preferably 0.8 to 3 mol with respect to 1 mol of the carboxylic acid derivative or the reactive derivative represented by the formula (I-2a, I-2b). Although it depends also on the reactive derivative and condensing agent used, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, aromatic hydrocarbons, such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, dioxane Ethers such as ether, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol and isopropanol, water, acetonitrile, N, N-dimethylformamide, N, N Dimethylacetamide, to dimethyl sulfoxide, in the -20 ℃ 150 ℃ in a solvent inert to the reaction such as pyridine may be preferably carried out at from 0 ℃ 100 ℃.

0.5-20 mol, preferably 0.8-5 mol of triethylamine, diisopropylethylamine, and N with respect to 1 mol of the carboxylic acid derivatives or the reactive derivatives thereof represented by formulas (I-2a, I-2b) at the time of reaction. Reaction is carried out in the presence of a base such as -methylmorpholine, N, N-dimethylaniline, N, N-diethylaniline, 4- (N, N-dimethylamino) pyridine, pyridine, picoline, lutidine, or the like. Sometimes it goes smoothly.

In addition, the amine compound represented by Formula (5) is well-known, or can be manufactured according to a well-known method.

The production intermediate thus obtained and the compound of the present invention can be purified by conventional separation means in synthetic chemistry such as extraction, precipitation, suspension washing, recrystallization, distillation, column chromatography and the like.

Medicinal composition

Compounds represented by the formula (I) or salts thereof are useful as prostaglandin D synthetase inhibitors, in particular hematopoietic prostaglandin D synthetases, because they can inhibit prostaglandin D synthase, in particular hematopoietic enzymes.

Accordingly, the present invention provides a pharmaceutical composition containing an effective amount of at least one of the compounds represented by the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

The present invention also provides the use of a compound represented by the formula (I) or a salt thereof as an inhibitor of a prostaglandin D synthetase, particularly an hematopoietic prostaglandin D synthetase.

As such, the compound represented by formula (I) or a salt thereof is useful for preventing or ameliorating undesirable symptoms caused by prostaglandin D2 or its metabolites derived from the enzyme in those having prostaglandin D synthetase inhibitory activity. . In particular, since the compound represented by the formula (I) or a salt thereof has an hematopoietic enzyme inhibitory action, a pharmaceutical composition comprising the compound or the salt thereof is used in mammals, especially humans, for bronchial asthma, pollen allergy and allergy. It is useful as a prophylactic and / or therapeutic agent for allergic diseases such as rhinitis, sinusitis, otitis media, allergic conjunctivitis, spring catarrh, atopic dermatitis, contact dermatitis and food allergies.

Compounds represented by the formula (I) or salts thereof include chronic obstructive pulmonary disease, interstitial pneumonia, irritable pneumonia, eosinophilic pneumonia, rheumatoid arthritis, deformable arthrosis, inflammatory bowel disease, skin disorders (dryness, eczema, erythema, Itching and acne, etc.), myositis, muscular dystrophy, restenosis after PTCA, reperfusion injury, graft rejection, etc., but are useful as a prophylactic and / or therapeutic agent for inflammatory diseases.

The compound represented by the formula (I) or a salt thereof can be expected to prevent the action of worsening Alzheimer's disease or brain injury and / or to improve the prognosis of brain injury.

The compounds represented by formula (I) or salts thereof are also useful for treating, preventing, or ameliorating mucus secretion disorders, reproductive disorders, blood coagulation disorders, pain, vision problems, obesity and immune diseases and autoimmune diseases. In addition, it can be used in cancer treatment because it can inhibit cell malignant transformation and metastasis of tumor growth, and it is possible to prevent the proliferative disorder of prostaglandin D2 or its metabolite intervening such as fibroblast proliferation, diabetic retinopathy and tumor angiogenesis. It is also useful in the treatment and / or prophylaxis. It can also be used for the treatment and / or prevention of infertility, dysmenorrhea, premature birth and eosinophil-related disorders in that it can also inhibit prostaglandin D2-induced smooth muscle contraction.

In order to apply the compound of the present invention or a salt thereof to the treatment or prophylaxis of the above-mentioned disease in a mammal including a human, the dosage is, of course, but the state or severity of the disease to be treated and the compound represented by the formula (I). It varies according to kind, the route of administration. It also varies depending on the age, body weight, general health of the individual patient, sex, meal, time of administration, rate of excretion, combination of medication and response. It is generally administered orally or parenterally. The dosage is generally an amount effective for the treatment of the disease, for example, a daily dose of about 0.001 to about 100 mg, preferably 0.01 to 50 mg / kg, per kilogram of body weight of a mammal, including a human. In some cases, dosages outside these ranges may be used.

The compound of the present invention or a salt thereof is mixed with an effective amount of a pharmaceutically acceptable carrier and solid preparations such as tablets, capsules, granules and powders, liquid preparations such as syrups and injections, ointments, lotions, gels and creams. It can be administered orally or parenterally (external, inhalation, subcutaneous injection, intravenous, intravenous injection, intramuscular injection, intra-bladder injection, intracranial injection, nasal drops, eye drops, suppositories) as external preparations such as agents.

As a pharmaceutically acceptable carrier, conventional various organic or inorganic carrier materials are used as a preparation material, and excipients, lubricants, binders, disintegrating agents, solvents in liquid formulations, dissolution aids, and suspending agents in solid preparations are used. , Isotonic agents, buffers, analgesics, and the like. Moreover, preparation additives, such as a preservative, antioxidant, a coloring agent, and a sweetener, can also be used as needed.

Examples of the most suitable excipient include lactose, D-mannitol, starch, crystalline cellulose, hard silicic anhydride, and the like. As the most suitable example of the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned. As the most suitable example of the binder, for example, crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone and the like can be mentioned. As a most suitable example of a disintegrating agent, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, etc. are mentioned, for example. Examples of the most suitable solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the most suitable dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Most suitable examples of suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, for example polyvinyl alcohol, poly Hydrophilic polymers such as vinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Most suitable examples of the buffer include buffers such as phosphates, acetates, carbonates, citrates and the like. As a most suitable example of a non-solvent agent, benzyl alcohol etc. are mentioned, for example. As the most suitable examples of the preservative, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dihydroacetic acid, sorbic acid and the like can be mentioned. As a most suitable example of antioxidant, a sulfite, an ascorbate, etc. are mentioned, for example.

(Example)

Although an Example demonstrates this invention concretely below, these do not limit the scope of the present invention.

In addition, ¹ H-NMR spectrum measured TMS (tetramethylsilane) as an internal standard, and showed the chemical shift by (delta) value (ppm). The chemical shift showed the absorption pattern, coupling constant (J value), and proton number in parentheses.

In addition, the following symbols are used about an absorption pattern. s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, m = multiplet, br = broad, brs = broad singlet.

In addition, the following symbols are used about the structural formula of a compound. Me = methyl, Et = ethyl, Ph = phenyl.

Example  One

5― Benzoyl -2-(2,4- Dimethylfuran -3 days)- Benzoimidazole (One)

In a methanol (3 mL) solution of 3,4-diaminobenzophenone (43 mg, 0.19 mmol), 2,4-dimethylfuran-3-carboxylic acid (30 mg, 0.21 mmol) and 4- (4,6-dimethoxy) chloride were used. 1,3,5-triazine-2-yl) -4-methylmorpholinium (65 mg, 0.23 mmol) was added, and after stirring overnight, the solvent was distilled off under reduced pressure. To the residue were added chloroform / methanol (7: 1) and saturated aqueous sodium carbonate solution, and after stirring for 30 minutes, the mixture was extracted with the same ratio of chloroform / methanol solvent, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

The residue obtained by distilling a solvent off under reduced pressure was purified using medium pressure silica gel flash column chromatography (chloroform: methanol = 99: 1). The resulting condensate was dissolved in acetic acid (4 ml), stirred at 80 ° C. overnight, cooled to room temperature and the solvent was distilled off to obtain a residue obtained by medium pressure silica gel flash column chromatography (chloroform: methanol = 99: 1). 5-Benzoyl-2- (2,4-dimethylfuran-3-yl) -benzoimidazole (22 mg, 35%) was obtained as a brown solid.

Melting Point 203-208 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.22 (s, 3H), 2.55 (s, 3H), 7.34 -7.93 (m, 9H), 8.05 (br, 1H).

Example  2

4― (5― Benzoylbenzoimidazole -2-day) -3,5- Dimethylfuran -2- Carboxamide (2)

Example  2 (1)

3,5-dimethyl-4 Ethoxycarbonylfuran -2- Carboxylic acid (2 raw materials)

2,4-dimethyl-5-formylfuran-3-carboxylic acid ethyl ester (1.78 g, 9.1 mmol), known in the literature, was dissolved in a mixture of acetic acid (32 mL) and water (8 mL), and amid sulfate (1.19) g, 12.2 mmol) was added and cooled to 0 ° C in an ice bath. After adding sodium chlorite and stirring for 2 hours, the precipitated solid was filtered by adding water into the system, and 3,5-dimethyl-4 ethoxycarbonylfuran-2-carboxylic acid (1.01 g, 52%) was white solid. As got.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.38 (t, J = 7.3 Hz, 3H), 2.56 (s, 3H), 2.64 (s, 3H), 4.33 (q, J = 7.3 Hz, 2H) .

Example  2 (2)

3,5-dimethyl-4 Ethoxycarbonylfuran -2- Carboxamide (2 raw materials)

To a pyridine (4 mL) solution of 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250 mg, 1.18 mmol) obtained in Example 2 (1), 1-ethyl-3- (3-dimethylamino Propyl) carbodiimide hydrochloride (248 mg, 1.30 mmol) and 1-hydroxybenzotriazole monohydrate (199 mg, 1.30 mmol) were added, followed by addition of 28% ammonia water (0.19 mL, 11.8 mmol) to 80 ° C. It heated and stirred for 4 hours. After cooling and stirring to room temperature, the precipitated solid was filtered by adding water into the system to give 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176 mg, 71%) as a white solid.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.37 (t, J = 7.0 Hz, 3H), 2.56 (s, 3H), 2.59 (s, 3H), 4.32 (q, J = 7.0 Hz, 2H) .

Example  2 (3)

4― (5― Benzoylbenzoimidazole -2-day) -3,5- Dimethylfuran -2- Carboxamide (2)

3,5-Dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176 mg, 0.83 mmol) obtained in Example 2 (2) was dissolved in ethanol (4 mL), and 0.13 mL of 4 N sodium hydroxide aqueous solution. Was added, and it stirred at 75 degreeC for 4 hours. It neutralized with 1N hydrochloric acid at room temperature, and the solid (crude carboxylic acid) which precipitated after removal of solvent distillation was filtered and used for the next reaction as it was.

To a methanol (3 mL) solution of 3,4-diaminobenzophenone (43 mg, 0.19 mmol) and the crude carboxylic acid (39 mg, 0.21 mmol) and 4- (4,6-dimethoxy-1,3,5-tri) chloride Azin-2-yl) -4-methylmorpholinium (65 mg, 0.23 mmol) was added, and after stirring overnight, the solvent was distilled off under reduced pressure. Chloroform / methanol (7: 1) and saturated aqueous sodium carbonate were added to the residue, followed by stirring for 30 minutes, followed by extraction with an equal ratio of chloroform / methanol solvent. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

The residue obtained by distilling a solvent off under reduced pressure was purified using medium pressure silica gel flash column chromatography (chloroform: methanol = 99: 1). The resulting condensate was dissolved in acetic acid (4 ml) and stirred at 80 ° C. overnight. After cooling to room temperature, the solvent was distilled off and purified using medium pressure silica gel flash column chromatography (chloroform: methanol = 99: 1), followed by 4- (5-benzoylbenzoimidazol-2-yl)- 3,5-Dimethylfuran-2-carboxamide (42 mg, 62%) was obtained as a yellow solid.

Melting Point: 143-146 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.67 (s, 3H), 2.72 (s, 3H), 5.76-6.22 (br, 2H), 7.85-7.47 (m, 9H).

Example  3

(4― (5― Benzoylbenzoimidazole -2-day) -3,5-dimethyl-2 Furanylcarbonyl ) Pyrrole Lidin (3)

Example  3 (1)

(3,5-dimethyl-4 Ethoxycarbonyl -2- Furanylcarbonyl ) Pyrrolidine (3 raw materials)

(3,5-Dimethyl-4-ethoxycarbonyl-2-furanylcarbonyl) pyrrolidine (89%) was white solid by using pyrrolidine in place of 28% ammonia water according to Example 2 (2). Obtained as.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.37 (t, J = 7.3 Hz, 3H), 1.92 (br, 4H), 2.49 (s, 3H), 2.57 (s, 3H), 3.62-3.73 ( m, 4H), 4.31 (q, J = 7.3 Hz, 2H).

Example  3 (2)

(4― (5― Benzoylbenzoimidazole -2-day) -3,5-dimethyl-2 Furanylcarbonyl ) Pyrrole Lidin (3)

(3,5-dimethyl-4-ethoxycarbonyl-2-furanylcarbonyl) instead of 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide according to Example 2 (3) By using pyrrolidine, (4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethyl-2-furanylcarbonyl) pyrrolidine (59%) was obtained as a pale yellow solid.

Melting Point: 112-114 ° C

¹ H-NMR (DMSO-d ₆ ): δ ppm 1.85 (br, 4H), 2.44, 2.46 (s and s, total 3H), 2.58, 2.60 (s and s, total 3H), 3.46 (br, 2H) , 3.74 (br, 2H), 7.42-7.99 (m, 8H), 12.56, 12.67 (s and s, total 1H).

Example  4

N- (3, 4- Methylenedioxyphenyl ) methyl -4-(5- Benzoylbenzoimidazole -2-day) -3,5- dimethylfuran -2 Carboxamide (4)

N- (3,4-methylenedioxyphenyl) methyl-4 (5-benzoylbenzoimidazol-2-yl) -3,5- by using piperonylamine instead of pyrrolidine according to Example 3 Dimethylfuran-2-carboxamide (87 mg, 87%) was obtained as a pale yellow solid.

Melting Point: 122-125 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.51, 2.53 (s and s, total 3H), 2.58, 2.61 (s and s, total 3H), 4.28-4.32 (m, 2H), 5.97 ( s, 2H), 6.75-6.89 (m, 3H), 7.42-7.99 (m, 8H), 8.71 (brs, 1H), 12.57, 12.68 (s and s, total 1H).

Example  5

4― (5― Benzoylbenzoimidazole -2-day)-pyrrole -2- Carboxylic acid (5)

Ethanol (45 ml), nitromethane (45 ml) and aluminum chloride (7.2 g) were added to pyrrole-2-carboxylic acid ethyl ester (3.0 g), and α, α-dichloromethylmethyl ether (3.2 g) was added to ice-cold cooling. It was dripped slowly and was left overnight at -20 degreeC. After the raw material disappeared, diethyl ether and water were added for extraction, and the obtained organic layer was concentrated under reduced pressure, and then dried under reduced pressure. The obtained solid was dissolved in N, N-dimethylformamide (20 ml), and N, N-dimethylform of 3,4-diaminobenzophenone (4.6 g) and sodium hydrogen sulfite (2.9 g) heated to 130 ° C. It was dripped slowly in the amide solution (30 mL). After heating at the bath temperature of 130 degreeC for 5 hours, the reaction liquid was cooled to room temperature, added to water and stirred, and the precipitated solid was filtered and heat-dried under reduced pressure.

The obtained solid was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL), and 4 N sodium hydroxide aqueous solution (15 mL) was added and heated to reflux for 4 hours. After the disappearance of the raw materials, the reaction solution was cooled to room temperature, neutralized by addition of hydrochloric acid, and the precipitated solid was filtered and dried under reduced pressure and dried under reduced pressure to thereby obtain 4- (5-benzoylbenzoimidazol-2-yl) -pyrrole-2-carboxylic acid. (5.3 g, 75%) was obtained as a pale yellow solid.

Melting Point: 239-241 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm): 7.40 (d, J = 1.6 Hz, 1H), 7.55-7.77 (m, 8H), 7.87 (s, 1H), 12.3 (br, 1H) .

Example  6

((4-(5- Benzoylbenzoimidazole -2-day)-pyrrole-2-day)-carbonyl) Pyrrolidine (6)

4- (5-benzoylbenzoimidazol-2-yl) -pyrrole-2-carboxylic acid (130 mg) obtained in Example 5 was dissolved in N, N-dimethylformamide (2 ml) and pyridine (2 ml), Pyrrolidine (56 mg), 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (112 mg), and 1-hydroxybenzotriazole monohydrate (80 mg) were added and heated at a bath temperature of 80 ° C. overnight. Stirred. After the disappearance of the raw materials, the mixture was left to cool to room temperature, and the reaction solution was added dropwise into water. The precipitated solid was filtered and dried under reduced pressure and dried under reduced pressure ((4- (5-benzoylbenzoimidazol-2-yl) -pyrrole-2-yl)- Carbonyl) pyrrolidine (118 mg, 78%) was obtained as a red solid.

Melting Point: 160-162 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.86 -2.04 (m, 4H), 3.48 -3.92 (m, 4H), 7.28 (s, 1H), 7.55 -7.77 (m, 9H), 12.0 (br, 1H), 12.8 (br, 1H).

Example  7

2- (2,4-dimethyl-pyrrole-3-yl) -5 Benzoylbenzoimidazole (7)

N, N-dimethylacetamide (5 ml) was heated to 130 ° C, 3.4-diaminobenzophenone (1.48 g) and sodium hydrogen sulfite (0.87 g) were added and stirred for 5 minutes, followed by 2,4-dimethyl- 3-formyl-pyrrole (1.03 g) was added, and it stirred at 130 degreeC for 8 hours. The solid precipitated by performing water-cooling stirring to room temperature, adding water in the system, and drying by heating under reduced pressure, 2- (2,4-dimethyl-pyrrole-3-yl) -5-benzoylbenzoimidazole (1.78) g, 81%) was obtained as a brown solid.

Melting point: 207-214 ° C

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.22 (s, 3H), 2.37 (s, 3H), 5.79 (s, 1H), 7.55-7.88 (m, 8H), 11.15 (s, 1H ), 12.97 (s, 1 H).

Example  8

2- (2-formyl-3,5-dimethyl-pyrrole-4-yl) -5 Benzoylbenzoimidazole (8)

Phosphoryl chloride (2.43 g) was slowly added dropwise to N, N-dimethylformamide (15.9 g) at room temperature, followed by stirring at room temperature for 30 minutes. N, N-dimethylformamide solution of 2- (2,4-dimethyl-pyrrole-3-yl) 5-benzoylbenzoimidazole (2.5 g) obtained in Example 7 was slowly added dropwise thereto. After stirring for 2 hours, 50 ml of 1 N sodium hydroxide solution was added, and the mixture was heated to 80 ° C and stirred for 2 hours. After the disappearance of the raw materials, the reaction solution was added dropwise to purified water, and the precipitated solid was filtered and dried under reduced pressure to obtain 2- (2-formyl-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole ( 1.63 g, 60%) was obtained as a brown solid.

Melting Point: 253-255 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.53 (s, 3H), 2.57 (s, 3H), 7.54--7.80 (m, 7H), 7.93 (s, 1H), 9.66 (s, 1H ), 12.30 (br, 1 H).

Example  9

2― (2― Acrylonitrile -3,5-dimethyl-pyrrole-4-yl) -5 Benzoylbenzoimida Sol (9)

2- (2-formyl-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole (105 mg) obtained in Example 8 was dissolved in tetrahydrofuran (2 ml), and diethyl Anomethylphosphonate (54 mg) and sodium methoxide (33 mg) were added, and it stirred at room temperature for 1 hour. Diethylcyanomethylphosphonate (54 mg) was added and heated at a bath temperature of 60 ° C. for 4 hours, followed by neutralization of the reaction with 0.1 N hydrochloric acid, followed by extraction with chloroform (5 mL) and water (2 mL). The organic layer was concentrated, and the residue was purified by medium pressure silica gel flash column chromatography (chloroform: ethyl acetate = 1: 1) and dried under reduced pressure to obtain 2- (2-acrylonitrile-3,5-dimethyl-pyrrole). -4-yl) -5-benzoylbenzoimidazole (61.6 mg, 55%) was obtained as a pale yellow solid.

Melting Point: 201-203 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.36 (s, 3H), 2.54 (s, 3H), 5.79 (d, J = 16.0 Hz, 1H), 7.48-7.98 (m, 10H), 11.85 (s, 1 H).

Example  10

4― (5― Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-carboxylic acid (10)

To a solution of 3,4-diaminobenzophenone (1.6 g) in N, N-dimethylacetamide (20 ml) sodium hydrogen sulfite (1.0 g) and 3,5-dimethyl-4-formylpyrrole-2-carboxylate Ester (1.5g) was added, it heated at 120 degreeC, and stirred for 10 hours. After cooling to room temperature, 5% aqueous sodium carbonate solution (60 g) was added, stirred at room temperature, and the precipitated solid was filtered and washed with water. The obtained solid was dissolved in ethanol (15 mL) and tetrahydrofuran (15 mL), and 4 N sodium hydroxide aqueous solution (20 mL) was added and heated to reflux for 12 hours. After the disappearance of the raw materials, the mixture was left to cool to room temperature, neutralized with 1 N hydrochloric acid, and the precipitated solid was filtered to afford 4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid (2.3 g, 90%) was obtained as a pale yellow solid.

Melting Point: 192―194 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.49 (s, 3H), 2.55 (s, 3H), 7.49-8.01 (m, 8H), 11.63 (brs, 1H), 11.68-12.57 (br) , 1H).

Example  11

N― methyl -N- (2 Dimethylaminoethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (11)

1-ethyl-3- in a pyridine (2 mL) solution of 4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid (150 mg, 0.42 mmol) obtained in Example 10. (3-dimethylaminopropyl) carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole monohydrate (70 mg, 0.46 mmol) were added, followed by N, N, N'-trimethylethylenediamine ( 43 mg, 0.42 mmol) was added and heated. It stirred at internal temperature of 60 degreeC for 5 hours, and it stirred to room temperature after that. The solvent was distilled off and purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2) and purified by N-methyl-N- (2-dimethylaminoethyl-4 (5-benzoylbenzoimimi). Dazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (112 mg, 61%) was obtained as a pale yellow amorphous.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.17 (s, 6H), 2.30 (s, 3H), 2.45, 2.47 (s and s, total 3H), 2.95-2.99 (m, 2H), 2.99 (s, 3H), 3.51 (t, J = 4.3 Hz, 2H), 7.56-7.89 (m, 8H), 7.89 (brs, 1H), 12.00, 12,14 (brs and brs, total 1H).

Example  12

4― (5― Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (12)

4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2 using a methanol solution of 7N ammonia instead of N, N, N'-trimethylethylenediamine in accordance with Example 11 -Carboxamide (55%) was obtained as a dark brown solid.

Melting Point: 188-190 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.47 (s, 3H), 2.49 (s, 3H), 6.99 (br, 2H), 7.54-7.77 (m, 7H), 7.91 (s, 1H ), 11.4 (s, 1 H), 12.02-12.39 (br 1H).

Example  13

2― (2― Cyano -3,5-dimethyl-pyrrole-4-yl) -5 Benzoylbenzoimidazole (13)

Example  13 (1)

5― Cyano -2,4-dimethylpyrrole-3 Carboxyaldehyde

Phosphorous oxychloride (10.2 ml, 110 mmol) was added dropwise to N, N-dimethylformamide (8.04 g, 110 mmol), stirred for 1 hour, and then 2-cyano-3,5, known as Synthesis (1999, 46), was stirred. A N, N-dimethylformamide (25 mL) solution of -dimethylpyrrole (12.0 g, 100 mmol) was added dropwise over 30 minutes. After stirring for 3 hours, the mixture was poured into ice water (about 500 g) and neutralized with solid sodium hydrogencarbonate. The reaction solution was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure after filtration of the desiccant was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 20 to 1: 5) to give 5-cyano-2,4-dimethylpyrrole. 3-Carboxyaldehyde (7.96 g, 54%) was obtained as a pale yellow solid.

Melting Point: 208-210 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.46 (s, 3H), 2.57 (s, 3H), 9.10 (brs, 1H), 9.97 (s, 1H).

Example  13 (2)

2― (2― Cyano -3,5-dimethyl-pyrrole-4-yl) -5 Benzoylbenzoimidazole (13)

3,4-diamino benzophenone (6.37 g, 30 mmol) was dissolved in N, N-dimethylacetamide (90 mL), sodium bisulfite (3.43 g, 33 mmol) was added, and the mixture was heated to 130 ° C. under stirring. N, N-dimethylacetamide (20 mL) solution of 5-cyano-2,4-dimethylpyrrole-3-carboxyaldehyde (4.89 g, 33 mmol) obtained in 13 (1) was added dropwise. After stirring the reaction solution at the same temperature for 12 hours, the solvent was evaporated under reduced pressure, saturated aqueous sodium bicarbonate solution and water were added, and the precipitated solid was filtered, washed with water and diethyl ether, and dried under reduced pressure. . The obtained coarse crystals were purified by medium-pressure silica gel flash column chromatography (methanol: chloroform = 1: 50 to 1:15) to give 2- (2-cyano-3,5-dimethyl-pyrrole-4-yl) -5-benzoyl Benzimidazole (7.85 g, 77%) was obtained as a pale yellow solid.

Melting Point: 159-163 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.41 (s, 3H), 2.52 (s, 3H), 7.52-7.98 (m, 8H), 12.12-12.48 (br, 2H).

Example  14

N― ( Methoxy ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Ka Leboxamide (14)

N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3 using O-methylhydroxylamine hydrochloride instead of N, N, N'-trimethylethylenediamine in accordance with Example 11 , 5-dimethylpyrrole-2-carboxamide (60%) was obtained as a brown solid.

Melting Point: 203-205 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.45, 2.45, 2.47, 2.48 (s and s and s and s, total 6H), 3.71 (s, 3H), 7.56-7.95 (m, 8H) , 10.75, 10.77 (s and s, total 1H), 11.46, 11.50 (s and s, total 1H), 12.14, 12.28 (s and s, total 1H).

Example  15

(N― Methoxy ―N― methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (15)

Example  15 (1)

3,5-Dimethyl-4 formyl Pyrrole -2- Carboxylic acid

3,5-Dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (19.52 g, 100 mmol), already known in the literature, is suspended in ethanol (100 mL) and dibasic sodium hydroxide aqueous solution (100 mL, 200 mmol), It stirred for 4 hours under heating reflux. After completion of the reaction, 200 ml of water and 100 ml of dihydrogen hydrochloric acid solution were added under ice cooling, and the precipitated solid was filtered, washed with water and diethyl ether, and dried under reduced pressure to obtain 3,5-dimethyl-4-formylpyrrole. 2-carboxylic acid (16.18 g, 97%) was obtained as a light brown solid.

Melting Point: 233-237 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.45 (s, 3H), 2.48 (s, 3H), 9.90 (s, 1H), 11.95 (brs, 1H), 12.58 (br, 1H).

Example  15 (2)

(N― Methoxy ―N― methyl ) -3,5-dimethyl-4-formyl Pyrrole -2- Carboxamide

The 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid (10.0 g, 60 mmol) obtained in Example 15 (1) was suspended in N, N-dimethylformamide (120 mL), and the 1-hydroxy group was cooled under ice cooling. Roxybenzotriazole monohydrate (9.65 g, 63 mmol), 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (12.65 g, 66 mmol), N, O-dimethylhydroxyamine hydrochloride (7.02 g, 72 mmol) and triethylamine (12.6 mL, 90 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the obtained reaction solution, extraction was performed with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by filtration and drying of the drying agent under reduced pressure was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 10 to 1: 3) to obtain (N-methoxy-N-methyl) -3, 5-Dimethyl-4-formylpyrrole-2-carboxamide (6.32 g, 50%) was obtained as a pale yellow solid.

Melting Point: 129-131 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.55 (s, 3H), 2.57 (s, 3H), 3.34 (s, 3H), 3.70 (s, 3H), 9.43 (brs, 1H), 10.04 ( s, 1 H).

Example  15 (3)

(N― Methoxy ―N― methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (15)

3,4-Diaminobenzophenone (5.31 g, 25 mmol) was dissolved in N, N-dimethylacetamide (70 mL), sodium hydrogen sulfite (2.86 g, 27.5 mmol) was added, and the mixture was heated and stirred at 130 ° C. N, N-dimethylacetamide of (N-methoxy-N-methyl) -3,5-dimethyl-4-formylpyrrole-2-carboxamide (5.78 g, 27.5 mmol) obtained in Example 15 (2) (15 mL) was added dropwise. After stirring the reaction solution at the same temperature for 16 hours, the solvent was evaporated under reduced pressure, saturated aqueous sodium bicarbonate solution and water were added, and the precipitated solid was filtered, washed with water and diethyl ether and dried under reduced pressure. . The resulting crude crystals were purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 100 to 1:20) to give (N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl). ) -3,5-dimethylpyrrole-2-carboxamide (7.25 g, 72%) was obtained as a pale yellow solid.

Melting Point: 127-132 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.43 (s, 3H), 2.50 (s, 3H), 3.26 (s, 3H), 3.63 (s, 3H), 7.50-8.00 (m, 8H ), 11.31 (brs, 1 H), 12.20 (br, 1 H).

Example  16

N― (3― Methoxypropyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (16)

N- (3-methoxypropyl) -4 (5-benzoylbenzoimidazol-2-yl) by using 3-methoxypropylamine instead of N, N, N'-trimethylethylenediamine according to Example 11 -3,5-dimethylpyrrole-2-carboxamide (61%) was obtained as a white solid.

Melting Point: 256-258 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.73-1.79 (m, 2H), 2.48 (s, 3H), 2.50 (s, 3H), 3.26 (s, 3H), 3.28-3.33 (m , 2H), 3.41 (t, J = 6.5 Hz, 2H), 7.42 (br, 1H), 7.59-7.93 (m, 8H), 11.37 (brs, 1H), 12.09, 12.24 (brs and brs, total 1H) .

Example  17

N- (3-dimethylaminopropyl) -4 (5- Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (17)

N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimimi by using N, N-dimethyl-1,3-propanediamine instead of N, N, N'-trimethylethylenediamine according to Example 11 Dazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (51%) was obtained as a white solid.

Melting Point: 238-248 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.63-1.69 (m, 2H), 2.16 (s, 6H), 2.31 (t, J = 7.1 Hz, 2H), 2.45 (s, 3H), 2.47 (s, 3H), 3.27-3.32 (m, 2H), 7.54-7.93 (m, 9H), 11.38 (s, 1H), 12.10, 12.24 (s and s, total 1H).

Example  18

N― (2― Acetamide  Ethyl) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (18)

N- (2-acetamideethyl) -4- (5-benzoylbenzoimidazol-2-yl)-by using N-acetylethylene diamine instead of N, N, N'-trimethylethylenediamine according to Example 11 3,5-dimethylpyrrole-2-carboxamide (67%) was obtained as a white solid.

Melting Point: 272-273 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.82 (s, 3H), 2.45 (s, 3H), 2.50 (s, 3H), 3.20-3.23 (m, 2H), 3.29-3.32 (m , 2H), 7.46-7.98 (m, 10H), 11.35, 11.39 (brs and brs, total 1H), 12.10, 12.25 (s and s, total 1H).

Example  19

N― (2― Ethoxycarbonylethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (19)

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazole-2) by using β-alanine ethyl ester hydrochloride in place of N, N, N'-trimethylethylenediamine in accordance with Example 11 I) -3,5-dimethylpyrrole-2-carboxamide (65%) was obtained as a purple solid.

Melting Point: 135-137 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.20 (t, J = 7.3 Hz, 3H), 2.47 (s, 3H), 2.50 (s, 3H), 2.58 (t, J = 6.8 Hz, 2H), 3.48-3.50 (m, 2H), 4.09 (q, J = 7.0 Hz, 2H), 7.36-7.98 (m, 10H), 11.4 (br, 1H).

Example  20

N― (1― Methoxycarbonylmethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide 20

N- (1-methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) by using glycinemethyl ester hydrochloride instead of N, N, N'-trimethylethylenediamine according to Example 11 -3,5-dimethylpyrrole-2-carboxamide (65%) was obtained as a purple solid.

Melting Point: 149-151 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.48 (s, 3H), 2.51 (s, 3H), 3.67 (s, 3H), 4.03 (d, J = 5.9 Hz, 2H), 7.37 8.02 (m, 9 H), 11.55 (br, 1 H).

Example  21

N― (2― Carboxyethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (21)

N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (300 mg) obtained in Example 19 was subjected to tetrahydro. It dissolved in furan (5 ml) and ethanol (5 ml), added 4 N sodium hydroxide aqueous solution (10 ml), and stirred at room temperature for 1 hour. After neutralizing the reaction solution with 4 N hydrochloric acid, the precipitated solid was filtered and dried under reduced pressure to obtain N- (2-carboxyethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5 -Dimethylpyrrole-2-carboxamide (211 mg, 75%) was obtained as a purple solid.

Melting Point: 256-258 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.40-2.50 (m, 2H), 2.47 (s, 3H), 2.50 (s, 3H), 3.38-3.53 (m, 2H), 7.54-7.95 (m, 10 H), 11.60 (br, 1 H).

Example  22

N― (1― Carboxymethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (22)

According to Example 21, N- (1 instead of N- (2-ethoxycarbonylethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide -Methoxycarbonylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide by using N- (1-carboxymethyl) -4- ( 5-Benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (67%) was obtained as a purple solid.

Melting Point: 274-276 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.47 (s, 3H), 2.54 (s, 3H), 3.79 (brs, 2H), 7.55-7.97 (m, 10H), 11.9 (br, 1H ).

Example  23

N― (2― Pyrrolidine -1 -yl-ethyl-4-(5- Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (23)

According to Example 11, N- (2-pyrrolidin-1-yl-ethyl) -4 by using 1- (2-amino ethyl) -pyrrolidine instead of N, N, N'-trimethylethylenediamine. (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (43%) was obtained as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.70 (br, 4H), 2.23 (s, 3H), 2.29 (s, 3H), 2.57 (br, 4H), 2.71 (br, 2H), 3.48 ( br, 2H), 6.96 (br, 1H), 7.46-8.19 (m, 9H), 10.36 (s, 1H).

Example  24

N- (2-piperidin-l-yl-ethyl) -4- (5- Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (24)

N- (2-piperidin-1-yl-ethyl) -4 by using 1- (2-amino ethyl) -piperidine in place of N, N, N'-trimethylethylenediamine according to Example 11 -(5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (71%) was obtained as a white solid.

 Melting Point: 230-237 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.39 (br, 2H), 1.51 (br, 4H), 2.40-2.50 (m, 5H), 2.97-3.00 (m, 1H), 3.32-3.37 (m, 2H), 7.27 (br, 1H), 7.56-7.93 (m, 8H), 11.45 (br, 1H), 12.1, 12.25 (s and s, total 1H).

Example  25

N- (cyclo Hexylmethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (25)

N- (cyclohexylmethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5 by using cyclohexylmethylamine instead of N, N, N'-trimethylethylenediamine according to Example 11 -Dimethylpyrrole-2-carboxamide (73%) was obtained as a white solid.

Melting Point: 254-255 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 0.91-0.97 (m, 2H), 1.17-11.22 (m, 3H), 1.51 (br, 1H), 1.63-1.75 (m, 5H), 2.46 (s, 3H), 2.49 (s, 3H), 3.10 (t, J = 6.1 Hz, 2H), 7.38-7.41 (m, 1H), 7.55-7.90 (m, 9H), 11.36 (s, 1H).

Example  26

N― (5― Methylisoxazole -3-work-4-(5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (26)

According to Example 11, N- (5-methylisoxazol-3-yl) -4 (5-) by using 3-amino-5-methylisoxazole instead of N, N, N'-trimethylethylenediamine. Benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (45%) was obtained as a pale yellow solid.

Melting Point: 271-273 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.41 (s, 3H), 2.57 (s, 3H), 2.59 (s, 3H), 6.73 (s, 1H), 7.59-7.99 (m, 8H ), 8.11 (s, 1H), 10.77 (s, 1H), 12.56 (s, 1H).

Example  27

N― (4― Cyanophenyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (27)

N- (4-cyanophenyl) -4 (5-benzoylbenzoimidazol-2-yl)-by using 4-cyanoaniline instead of N, N, N'-trimethylethylenediamine according to Example 11 3,5-dimethylpyrrole-2-carboxamide (38%) was obtained as a pale yellow solid.

Melting Point: 252-254 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.51 (s, 3H), 2.58 (s, 3H), 7.58-8.07 (m, 12H), 10.6 (br, 1H).

Example  28

N-(indol -5-day) -4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-carboxamide (28)

N- (indol-5-yl) -4 (5-benzoylbenzoimidazol-2-yl) -3 by using 5-aminoindole instead of N, N, N'-trimethylethylenediamine according to Example 11 , 5-dimethylpyrrole-2-carboxamide (63%) was obtained as a pale yellow solid.

Melting Point: 167-169 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.53, 2.55 (s and s, 3H), 2.58, 2.59 (s and s, 3H), 6.40 (t, J = 2.2 Hz, 1H), 7.29 -7.38 (m, 3H), 7.56-7.95 (m, 9H), 9.30 (d, J = 4.9 Hz, 1H), 11.00 (brs, 1H), 11.56, 11.60 (s and s, total 1H), 12.14, 12.29 (s and s, total 1 H).

Example  29

N- (3, 4- Methylenedioxyphenyl -1-day -4-(5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (29)

By using 3,4-methylenedioxyaniline instead of N, N, N'-trimethylethylenediamine according to Example 11, N- (3,4-methylenedioxyphenyl-5-yl) -4 (5-) Benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (55%) was obtained as a pale yellow solid.

Melting Point: 160-162 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.52 (s, 3H), 2.55 (s, 3H), 6.00 (s, 2H), 6.87 (d, J = 8.3 Hz, 1H), 7.07 ( dd, J = 2.1, 8.3 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.55-7.77 (m, 8H), 7.91 (brs, 1H), 9.41 (s, 1H).

Example  30

N- (2,3- Dihydrobenzofuran -5-work-4-(5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (30)

N- (2,3-dihydrobenzofuran-5-yl)-by using 2,3-dihydro-5-aminobenzofuran in place of N, N, N'-trimethylethylenediamine according to Example 11 4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (63%) was obtained as a pale yellow solid.

Melting Point: 170-172 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.50 (s, 3H), 2.55 (s, 3H), 3.19 (t, J = 8.4 Hz, 2H), 4.52 (t, J = 8.4 Hz, 2H), 6.73 (d, J = 8.6 Hz, 1H), 7.30 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.55-7.91 (m, 9H), 11.56 (br, 1H), 12.14, 12.28 (s and s, total 1H).

Example  31

N― ( Benzothiazole -6-work-4-(5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (31)

N- (benzothiazol-6-yl) -4- (5-benzoylbenzoimidazole-2) by using 6-aminobenzothiazole instead of N, N, N'-trimethylethylenediamine according to Example 11 I) -3,5-dimethylpyrrole-2-carboxamide (75%) was obtained as a pale yellow solid.

Melting Point: 155-157 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.55 (s, 3H), 2.56 (s, 3H), 7.55-8.08 (m, 11H), 8.62 (s, 1H), 9.27 (s, 1H ), 9.79 (s, 1 H), 11.71 (s, 1 H).

Example  32

N- (3,4-ethylenedioxyphenyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (32)

N- (3,4-ethylenedioxyphenyl) -4- (5-benzoylbenzoimidazole by using 3,4-ethylenedioxyaniline instead of N, N, N'-trimethylethylenediamine according to Example 11 -2 -yl) -3,5-dimethylpyrrole-2-carboxamide (63%) was obtained as a pale yellow solid.

Melting Point: 145-147 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.53 (s, 3H), 2.55 (s, 3H), 4.13-4.30 (m, 4H), 6.81 (d, J = 9.0 Hz, 1H), 7.09 (dd, J = 9.0, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.55-7.98 (m, 8H), 9.32, 9.34 (s and s, total 1H), 11.55, 11.59 (s and s, total 1H), 12.14, 12.29 (s and s, total 1H).

Example  33

N― (2― Pyridylmethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole -2- Carboxamide (33)

N- (2-pyridylmethyl) -4- (5-benzoylbenzoimidazol-2-yl)-by using 2-aminomethylpyridine in place of N, N, N'-trimethylethylenediamine according to Example 11 3,5-Dimethylpyrrole-2-carboxamide (87%) was obtained as a pale yellow amorphous.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.48, 2.50 (s and s, total 3H), 2.55, 2.57 (s and s, total 3H), 4.59 (br, 2H), 7.28-8.05 ( m, 12H), 8.53 (s, 1H), 11.51 (br, 1H), 12.14, 12.28 (s and s, total 1H).

Example  34

N- (2- Pyridyl Ethyl) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (34)

N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzo) by using 2- (2-amino ethyl) pyridine instead of N, N, N'-trimethylethylenediamine according to Example 11 Imidazole-2-yl) -3,5-dimethylpyrrole-2-carboxamide (54%) was obtained as a white solid.

Melting Point: 237.5-243.9 ° C

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.44 (s, 3H), 2.46 (s, 3H), 2.99-3.03 (m, 2H), 3.62-3.64 (m, 2H), 7.23 -7.92 (m, 12H), 8.53 (br, 1H), 11.4 (s, 1H), 12.1 (s, 1H).

Example  35

N- (3, 4- Dichlorobenzyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (35)

N- (3,4-dichlorobenzyl) -4- (5-benzoylbenzoimidazole-2) by using 3,4-dichlorobenzylamine instead of N, N, N'-trimethylethylenediamine according to Example 11 I) -3,5-dimethylpyrrole-2-carboxamide (63%) was obtained as a purple solid.

Melting Point: 141-143 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.48 (s, 3H), 2.53 (s, 3H), 4.46 (d, J = 5.4 Hz, 2H), 7.27-8.15 (m, 12H), 11.51 (s, 1 H).

Example  36

N- (3, 4- Dimethoxybenzyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (36)

By using 3,4-dimethoxybenzylamine instead of N, N, N'-trimethylethylenediamine according to Example 11, N- (3,4-dimethoxybenzyl) -4- (5-benzoylbenzoimidazole- 2-yl) -3,5-dimethylpyrrole-2-carboxamide (68%) was obtained as a purple solid.

Melting Point: 120-122 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.47 (s, 3H), 2.54 (s, 3H), 3.73 (s, 3H), 3.75 (s, 3H), 4.41 (d, J = 5.4 Hz, 2H), 6.85-6.98 (m, 3H), 7.55-7.95 (m, 8H), 11.44 (brs, 1H).

Example  37

N- (3, 4- Methylenedioxyphenylmethyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (37)

N- (3,4-methylenedioxyphenylmethyl) -4- (5-benzoylbenzoimidazole-2) by using piperonylamine instead of N, N, N'-trimethylethylenediamine according to Example 11 I) -3,5-dimethylpyrrole-2-carboxamide (56%) was obtained as a pale yellow solid.

Melting Point: 165-167 ° C

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.47 (s, 3H), 2.50 (s, 3H), 4.38 (d, J = 5.6 Hz, 2H), 5.99 (s, 2H), 6.81 6.93 (m, 3 H), 7.55-77.7 (m, 7 H), 7.90 (brs, 1 H).

Example  38

N― (2,3,4,5― Tetrahydro -3-oxo- Pyridazine -6-day methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (38)

According to Example 11, N- (2,3,4,5 by using 6-aminomethyl-4,5-dihydropyridazine-3 (2H) -one instead of N, N, N'-trimethylethylenediamine -Tetrahydro-3 -oxo-pyridazine-6-yl-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (14%) Was obtained as a pink solid.

Melting Point: 287 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.29 -2.33 (m, 2H), 2.46 -2.50 (m, 2H), 2.50 (s, 6H), 4.10 (s, 2H), 7.56 -7.93 (m, 8H), 10.60 (s, 1H), 11.48 (br, 1H), 12.13, 12.28 (s and s, total 1H).

Example  39

((4-(5- Benzoylbenzoimidazole -2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) pyrrolidine (39)

By using pyrrolidine in place of N, N, N'-trimethylethylenediamine according to Example 11 ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) ) -Carbonyl) pyrrolidine (73%) was obtained as a pale yellow solid.

Melting Point: 155-157 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.85 (br, 4H), 2.48 (s, 3H), 2.50 (s, 3H), 3.48 (br, 4H), 7.55-77.7 (m, 8H ), 7.89 (s, 1 H), 11.3 (s, 1 H).

Example  40

((4- (5 -Benzoylbenzoimidazol -2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) morpholine (40)

By using morpholine instead of N, N, N'-trimethylethylenediamine according to Example 11 ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -Carbonyl) morpholine (65%) was obtained as a pale yellow solid.

Melting Point: 201-203 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.30 (s, 3H), 2.48 (s, 3H), 3.54 (brs, 4H), 3.61 (brs, 4H), 7.55-77.7 (m, 8H ), 7.91 (s, 1 H), 11.51 (brs, 1 H).

Example  41

((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4 Phenylpiperazine (41)

According to Example 11, by using 1-phenylpiperidine in place of N, N, N'-trimethylethylenediamine ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole) 2-yl) -carbonyl) -4-phenylpiperazine (70%) was obtained as an ocher solid.

Melting Point: 145-147 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.33 (s, 3H), 2.23-2.57 (m, 2H), 2.50 (s, 3H), 3.01-3.54 (m, 4H), 3.70 (br) , 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 7.15-7.28 (m, 2H), 7.55-8.08 (m, 8H), 11.43 (brs, 1H).

Example  42

((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) pyrazoline (42)

By using pyrazoline in place of N, N, N'-trimethylethylenediamine according to Example 11 ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -Carbonyl) pyrazoline (73%) was obtained as a pale yellow solid.

Melting Point: 148-150 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.47 (s, 3H), 2.49 (s, 3H), 2.85-3.00 (m, 2H), 3.79-3.93 (m, 2H), 7.29 (s , 1H), 7.54-7.80 (m, 7H), 7.91 (s, 1H), 11.20 (s, 1H), 12.23 (br, 1H).

Example  43

((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4-hydroxypiperidine (43)

By using 4-hydroxypiperidine in place of N, N, N'-trimethylethylenediamine according to Example 11 ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole) -2-yl) -carbonyl) -4-hydroxypiperidine (55%) was obtained as a pale yellow solid.

Melting point: 288-290 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.27-1.48 (m, 2H), 1.69-1.87 (m, 2H), 2.28 (s, 3H), 2.47 (s, 3H), 3.14-3.35 (m, 2H), 3.65-3.97 (m, 3H), 4.78 (s, 1H), 7.52-7.96 (m, 8H), 11.43 (s, 1H), 11.85-12.33 (br, 1H).

Example  44

((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4 Ethoxycarbonylpiperidine (44)

According to Example 11, by using isonipecotinic acid ethyl ester instead of N, N, N'-trimethylethylenediamine ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole) 2-yl) -carbonyl) -4-ethoxycarbonylpiperidine (72%) was obtained as a brown solid.

Melting Point: 272-274 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.27 (t, J = 7.1 Hz, 3H), 1.74 (br, 2H), 1.97 (br, 2H), 2.35 (brs, 3H), 2.54 (br, 3H), 2.58-2.59 (m, 1H), 3.06-3.11 (br, 2H), 4.15 (q, J = 7.1 Hz, 2H), 4.22 (br, 2H), 7.47-8.15 (m, 8H), 10.52 (br, 1H), 11.53, 11.60 (s and s, total 1H).

Example  45

((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxylic acid (45)

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) -4-ethoxycarbonylpiperidine obtained in Example 44 (4.19 g) And 10.8 mmol) of ethanol (15 mL) were added 1 N sodium hydroxide solution (16.2 mL, 16.2 mmol) and stirred at 100 ° C for 4 hours. After cooling to room temperature, the mixture was neutralized with 6N hydrochloric acid (12 ml, 16.2 mmol). The precipitated solid was filtered and dried under reduced pressure ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxylic acid ( 3.02 g, 78%) was obtained as white crystals.

Melting Point: 267-271 ° C

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.74 (m, 2H), 1.98 (d, J = 10 Hz, 2H), 2.35 (s, 3H), 2.53 (s, 3H), 2.58-2.59 (m , 1H), 3.14 (dd, J = 10, 10 Hz, 2H), 4.20 (d, J = 10 Hz, 2H), 7.49-8. 18.1 (m, 8H), 10.39 (br, 1H), 11.50 (br, 1H) .

Example  46

N― Dimethylaminoethyl -1-((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (46)

((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxylic acid (70 mg, 0.15 mmol) obtained in Example 45 To the pyridine (4 mL) solution of 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole monohydrate (25 mg, 0.16 mmol) Then, N, N-dimethylethylenediamine (13 mg, 0.15 mmol) was added and heated. It stirred at internal temperature of 60 degreeC for 10 hours, and stirred to room temperature after that. The solvent was distilled off and purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2) and purified by N-dimethylaminoethyl-1-((4- (5-benzoylbenzoimidazole-2). -Yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide (44 mg, 55%) was obtained as white crystals.

Melting Point: 258-260 ° C

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.48-1.72 (m, 4H), 2.13 (s, 6H), 2.26 (brs, 3H), 2.42, 2.46 (brs and brs, total 3H), 2.94-3.18 (m, 3H), 3.32 (br 4H), 4.09 (br, 2H), 7.55-7.90 (m, 8H), 11.42, 11.46 (s and s, total 1H), 12.02, 12.17 (s and s , total 1H).

Example  47

N― methyl -N- (2 Dimethylaminoethyl ) -1-((4-(5-) Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (47)

By using N, N, N'-trimethylethylenediamine in place of N, N-dimethylethylenediamine according to Example 46, N-methyl-N- (2-dimethylaminoethyl) -1-((4- (5- Benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide (68%) was obtained as white crystals.

Melting Point: 264-266 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.75 (br, 4H), 2.22 (s, 3H), 2.27 (s, 3H), 2.32, 2.34 (s and s, total 3H), 2.40 (t, J = 4.6 Hz, 1H), 2.47 (t, J = 4.6 Hz, 1H), 2.52, 2.54 (s and s, total 3H), 2.85 (br, 1H), 2.98-3.08 (m, 2H), 3.11 ( s, 3H), 3.42-3.44 (m, 2H), 4.30 (m, 2H), 7.51-8.07 (m, 8H), 11.14 (s, 1H), 11.80 (s, 1H).

Example  48

N- (3-dimethylaminopropyl) -1-((4- (5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (48)

By using N, N'-dimethyl-1,3-propanediamine instead of N, N-dimethylethylenediamine according to Example 46, N- (3-dimethylaminopropyl) -1-((4- (5-benzoyl) Benzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide (41%) was obtained as a white solid.

Melting Point: 247-251 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.49-1.73 (m, 6H), 2.10 (s, 6H), 2.18 (t, J = 7.3 Hz, 2H), 2.27, 2.28 (s and s total 3H), 2.39, 2.50 (s and s, total 3H), 2.95-3.12 (m, 5H), 4.11 (br, 2H), 7.56-7.91 (m, 8H), 11.42, 11.46 (brs and brs, total 1H), 12.02, 12.17 (s and s, total 1H).

Example  49

N― (3― Methoxypropyl ) -1-((4-(5-) Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide (49)

According to Example 46, N- (3-methoxypropyl) -1-((4- (5-benzoylbenzoimidazol-2-yl) by using 3-methoxypropylamine instead of N, N-dimethylethylenediamine ) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide (98%) was obtained as a white solid.

Melting Point: 289-291 ° C

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.72-1.87 (m, 6H), 2.34, 2.36 (s and s, total 3H), 2.37 (m, 1H), 2.53, 2.55 (s and s, total 3H), 3.03 (dd, J = 12.7, 12.7 Hz, 2H), 3.25-3.38 (m, 2H), 3.34 (s, 3H), 3.46 (t, J = 5.7 Hz, 2H), 4.32 (d, J = 12.7 Hz, 2H), 6.82 (brs, 1H), 7.48-7.82 (m, 7H), 8.00, 8.16 (s and s, total 1H), 10.41, 10.46 (brs and brs, total 1H), 11.50, 11.56 (brs and brs, total 1 H).

Example  50

N--cyclo Hexylmethyl -1-((4-(5- Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -carbonyl) piperidine-4 Carboxamide 50

According to Example 46, by using cyclohexylmethylamine instead of N, N-dimethylethylenediamine, N-cyclohexylmethyl-1-((4- (5-benzoylbenzoimidazol-2-yl) -3,5- Dimethylpyrrole-2-yl) -carbonyl) piperidine-4-carboxamide (64%) was obtained as a white solid.

Melting Point: 274-276 ℃

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.71-1.86 (m, 4H), 1.95 (br, 5H), 2.33, 2.34 (s and s, total 3H), 2.53, 2.54 (s and s, total 3H), 2.59 (br, 2H), 2.99 (br, 5H), 3.30 (br, 4H), 4.29 (d, J = 12.0 Hz, 2H), 7.47-7.80 (m, 8H), 7.98, 8.12 (s and s, total 1H), 10.78, 10.82 (brs and brs, total 1H), 11.67, 11.75 (br and br, total 1H).

Example  51

5― Benzoyl -2-(pyrrole-2-day) Benzoimidazole (51)

N, N-dimethylacetamide (5 ml) was heated to 130 ° C., 3,4-diaminobenzophenone (150 mg, 0.71 mol) and sodium hydrogen sulfite (89 mg, 0.85 mol) were added and stirred for 5 minutes. 2-formyl-pyrrole (81 mg, 0.85 mol) was added, and it stirred at 130 degreeC for 1.5 hours. After cooling to room temperature, the precipitated crystals were filtered by adding water into the system to obtain 5-benzoyl-2- (pyrrole-2-yl) -benzoimidazole (129 mg, 63%) as a pale yellow solid.

Melting Point: 128-133 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 6.26 (s, 1H), 6.96 (s, 1H), 7.04 (s, 1H), 7.55-77.7 (m, 8H), 7.89 (s, 1H ), 11.92 (s, 1 H).

Example  52

5― Benzoyl -2-(3,5-dimethylpyrrole-2-yl)- Benzoimidazole (52)

To a pyridine (3 mL) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol), 3,5-dimethylpyrrole-2-carboxylic acid (99 mg, 0.71 mmol) was added, and 1-ethyl-3 (( 3-dimethylaminopropyl) carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were added and heated to 70 ° C. and stirred overnight. After cooling to room temperature, the solvent was distilled off and the residue was purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2), and the resulting oily substance was diluted with acetic acid (3 ml). It melt | dissolved in and heated and stirred at 100 degreeC for 8 hours. After cooling to room temperature, the solvent was distilled off and the mixture was purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2), and purified by 5-benzoyl-2- (3,5-dimethylpyrrole-2). -Yl) -benzoimidazole (34 mg, 15% / 2 steps) was obtained as a yellow solid.

Melting Point: 225-229 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.23 (s, 3H), 2.37 (s, 3H), 5.79 (s, 1H), 7.55-7.88 (m, 8H), 11.09, 11.21 (s and s, total 1H), 11.90, 12.06 (s and s, total 1H).

Example  53

5― (5― Benzoylbenzoimidazole -2-day) -2,4- dimethylpyrrole-3 Ethyl carboxylate  Ester (53)

Example  53 (1)

5-Formyl-2,4-dimethyl-pyrrole-3-carboxylic acid ethyl ester ( 53 raw materials )

2,4-diethoxycarbonyl-3,5-dimethylpyrrole (2.0 g) was dissolved in ethanol (20 mL), 1 N sodium hydroxide solution (20 mL) was added, and the mixture was heated and stirred overnight at a bath temperature of 80 ° C. . After cooling to room temperature, the reaction solution was neutralized with hydrochloric acid, and the precipitated solid was filtered and dried under reduced pressure. The obtained solid was dissolved in trifluoroacetic acid (20 ml), heated and stirred at a bus temperature of 40 ° C. for 1 hour, and then triethyl orthogiric acid (2.5 ml) was slowly added dropwise under ice cooling, and the temperature was raised to room temperature, followed by stirring for 2 hours. . After concentration under reduced pressure, the solvent was distilled off, and the residue was added to saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was filtered. The obtained solid was purified by medium pressure silica gel flash column chromatography (hexane: ethyl acetate = 5: 1-1: 1), and it dried by heat-drying under reduced pressure, 5-formyl- 2, 4- dimethyl- pyrrole- 3-carboxylic acid ethyl ester (1.21 g, 74%) was obtained as a pale yellow solid.

Example  53 (2)

5― (5― Benzoylbenzoimidazole -2-day) -2,4- dimethylpyrrole-3 Ethyl carboxylate  Ester (53)

5-formyl-2,4-dimethyl obtained in Example 53 (1) with sodium hydrogen sulfite (101 mg) in a N, N-dimethylacetamide (5 ml) solution of 3,4-diaminobenzophenone (160 mg). -Pyrrole-3-carboxylic acid ethyl ester (146 mg) was added, and it heated at 120 degreeC and stirred for 10 hours. After cooling to room temperature, 5% aqueous sodium carbonate solution (6 ml) was added, stirred at room temperature, and the precipitated solid was filtered to give 5- (5-benzoylbenzoimidazol-2-yl) -2,4-dimethylpyrrole-3. Carboxylic acid ethyl ester (248 mg, 85%) was obtained as a pale yellow solid.

Melting Point: 185-187 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.32 (t, J = 7.2 Hz, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 4.29 (q, J = 7.2 Hz, 2H), 7.55-77.7 (m, 7H), 7.95 (s, 1H), 11.8 (brs, 1H).

Example  54

5― (5― Benzoylbenzoimidazole -2-day) -2,4- dimethylpyrrole-3 Carboxylic acid (54)

5- (5-benzoylbenzoimidazol-2-yl) -2,4-dimethylpyrrole-3-carboxylic acid ethyl ester (200 mg) obtained in Example 53 (2) was diluted with ethanol (5 ml) and tetrahydrofuran (5). ML), and added 4 N sodium hydroxide aqueous solution (10 mL) and heated to reflux for 12 hours. After the disappearance of the raw materials, the mixture was left to cool to room temperature, neutralized with 1N hydrochloric acid, and the precipitated solid was filtered to afford 5- (5-benzoylbenzoimidazol-2-yl) -2,4-dimethylpyrrole-3-carboxylic acid (139 mg, 75). %) Was obtained as a pale yellow solid.

Melting Point:〉 300 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.50 (s, 3H), 2.63 (s, 3H), 7.55-77.7 (m, 8H), 7.90 (s, 1H), 12.20 (br, 1H ).

Example  55

2― (5― Pyrrolidine -1 day- methyl -Furan -2-day -5 Benzoylbenzoimidazole (55)

Example  55 (1)

5― Pyrrolidine -1 day- methyl -Furan-2-carboxylic acid ethyl ester ( 55 raw materials )

Pyrrolidine (0.75 g, 10.6 mmol) was added to a solution of 5-chloromethylfuran-2-carboxylic acid ethyl ester (1.0 g, 5.3 mmol) in N, N-dimethylacetamide (15 ml), and the mixture was kept at room temperature for 24 hours. Stirred. After distilling off the solvent, the residue was purified by medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2), and purified by 5-pyrrolidin-1-yl-methyl-furan-2-carboxylic acid ethyl ester (793 mg). , 67%) was obtained.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 1.70 (br, 3H), 2.54 (br, 4H), 3.17 (br, 4H), 3.70 (s, 2H), 4.29 (br, 2H), 6.59 (s, 1 H), 6.75 (br, 1 H).

Example  55 (2)

5― Pyrrolidine -1 day- methyl -Furan-2-carboxylic acid ( 55 raw materials )

5-Pyrrolidin-l-yl-methyl-furan-2-carboxylic acid ethyl ester (770 mg, 3.45 mmol) obtained in Example 55 (1) was dissolved in ethanol (4 mL), and sodium hydroxide aqueous solution (5.17) was prescribed. Ml) was added dropwise and stirred overnight. After neutralizing with 1 N hydrochloric acid (5.17 mL), ethanol was distilled off and dried to dry 5-Pyrrolidin-1-yl-methyl-furan-2-carboxylic acid (1.08 g, containing 38% weight sodium chloride) mixed with sodium chloride , quant.) was obtained as a white solid and used for the next reaction as it was.

Example  55 (3)

2― (5― Pyrrolidine -1 day- methyl -Furan -2-day -5 Benzoylbenzoimidazole (55)

To a pyridine (3 mL) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol) was added 5-pyrrolidin-1-yl-methyl-furan-2-carboxylic acid (62% purity, 223 mg, 0.71 mmol). In addition, 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added and heated to 70 ° C. And stirred overnight. After cooling to room temperature, the solvent was distilled off and purified as it was using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2). The mixture was heated and stirred for 8 hours. After cooling to room temperature, the solvent was distilled off and the mixture was purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2), and purified by 2- (5-pyrrolidin-1-yl-methyl). Furan-2-yl) -5-benzoylbenzoimidazole (143 mg, 55% / 2 steps) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.90 (br, 4H), 2.81 (br, 4H), 3.88 (s, 2H), 6.45 (d, J = 3.5 Hz, 1H), 7.19 (d, J = 3.5 Hz, 1H), 7.44-7.84 (m, 8H), 8.10 (s, 1H)

Example  56

2― (5― Dimethylaminomethyl -Furan -2-day -5 Benzoylbenzoimidazole (56)

According to Example 55, 2- (5-dimethylaminomethyl-furan-2-yl) -5-benzoylbenzoimidazole (203 mg, 83%) was obtained as pale yellow amorphous by using dimethylamine instead of pyrrolidine.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.21 (s, 6H), 3.59 (s, 2H), 6.56 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 7.54-7.92 (m, 8H), 13.23 (br, 1H).

Example  57

5― (5― Benzoylbenzoimidazole -2-day)-furan -2 Carboxylic acid (57)

N, N-dimethylacetamide (5 ml) was heated to 130 ° C, 3,4-diaminobenzophenone (63 mg, 0.30 mmol) and sodium hydrogen sulfite (37 mg, 0.36 mmol) were added and stirred for 5 minutes. 5-formyl-furan-2-carboxylic acid (50 mg, 0.36 mmol) was added, and it stirred at 130 degreeC for 1.5 hours. The solid precipitated by performing water-cooling stirring to room temperature and adding water in the system, and 5- (5-benzoylbenzoimidazol-2-yl) -furan-2-carboxylic acid (63 mg, 64%) were pale yellow solid. Obtained as.

Melting Point: 170 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.39-8.01 (m, 10H), 13.61 (s, 1H).

Example  58

2― (5― Bromo -Furan -2-day -5 Benzoylbenzoimidazole (58)

2- (5-bromo-furan-2-yl) -5-benzoylbenzoimidazole by using 5-bromofuran-2-carboxylic acid instead of 2,4-dimethylfuran-3-carboxylic acid according to Example 1 (92%) was obtained as a yellow solid.

Melting Point: 167-172 ° C

¹ H-NMR (CDCl ₃ ): δ (ppm) 6.59 (d, J = 3.4 Hz, 1H), 7.23 (d, J = 3.4 Hz, 1H), 7.41-7.81 (m, 8H), 8.06 (s, 1H).

Example  59

(4― (5― Benzoylbenzoimidazole -2-day) -2- Furanylcarbonyl ) Pyrrolidine (59)

To a pyridine (4 mL) solution of 5- (5-benzoylbenzoimidazol-2-yl) -furan-2-carboxylic acid (100 mg, 0.30 mmol) obtained in Example 57, 1-ethyl-3- (3-dimethylamino Propyl) carbodiimide hydrochloride (63 mg, 0.33 mmol) and 1-hydroxybenzotriazole monohydrate (51 mg, 0.33 mmol) were added, followed by addition of pyrrolidine (21 mg, 0.30 mmol) and heating. It stirred at 70 degreeC for 6 hours, and it stirred to room temperature after that. The solvent was distilled off and purified using medium pressure silica gel flash column chromatography (NH silica gel; chloroform: methanol = 98: 2), and (4- (5-benzoylbenzoimidazol-2-yl) -2-furanylcar Bonyl) pyrrolidine (102 mg, 88%) was obtained as a brown oily material.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.95-2.10 (m, 4H), 3.68 (t, J = 6.8 Hz, 2H), 3.82 (t, J = 6.8 Hz, 2H), 7.04 (d, J = 3.7 Hz, 1H), 7.32 (d, J = 3.7 Hz, 1H), 7.45-7.83 (m, 8H), 8.12 (s, 1H).

Example  60

5― (5― Benzoylbenzoimidazole -2-day)-furan -2 Carboxamide (60)

According to Example 59, 5- (5-benzoylbenzoimidazol-2-yl) -furan-2-carboxamide (96%) was obtained as a brown oily substance by using 28% ammonia water instead of pyrrolidine.

¹ H-NMR (CDCl ₃ ): δ (ppm) 6.58-8.19 (m, 12H), 12.76 (s, 1H).

Example  61

N― (2― Dimethylaminoethyl ) -5- (5 Benzoylbenzoimidazole -2-day)-furan-2-carboxamide (61)

By using N, N-dimethylethylenediamine instead of pyrrolidine according to Example 59, (N- (2-dimethylaminoethyl) -5- (5-benzoylbenzoimidazol-2-yl) -furan-2- Carboxamide (64%) was obtained as a brown oily substance.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.32 (s, 6H), 3.22 (br, 2H), 3.56 (br, 2H), 5.51 (br, 1H), 7.19-8.09 (m, 11H).

Example  62

N- (3, 4- Methylenedioxyphenylmethyl ) -5- (5 Benzoylbenzoimidazole -2-day)-furan -2 Carboxamide (62)

N- (3,4-methylenedioxyphenylmethyl) -5- (5-benzoylbenzoimidazol-2-yl) -furan-2- by using piperonylamine instead of pyrrolidine according to Example 59 Carboxamide (77%) was obtained as a brown oily substance.

¹ H-NMR (CDCl ₃ ): δ (ppm) 4.42 (s, 2H), 5.85 (s, 2H), 6.63-7.96 (m, 15H).

Example  63

(4― (5― Benzoylbenzoimidazole -2-day) -2- Furanylcarbonyl ) Thiazolidine (63)

(4- (5-benzoylbenzoimidazol-2-yl) -2-furanylcarbonyl) thiazolidine (64%) was obtained as a brown oily substance by using thiazolidine in place of pyrrolidin according to Example 59. Obtained as.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.25 (s, 2H), 3.12-3.26 (m, 4H), 7.28 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.48-7.82 (m, 8H), 8.08 (s, 1H).

Example  64

(N, N-dimethyl) -4 (5-) Benzoylbenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-carboxamide (64)

(N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3, by using a 40% aqueous dimethylamine solution in place of N, N, N'-trimethylethylenediamine according to Example 11 5-dimethylpyrrole-2-carboxamide (95%) was obtained as a pale yellow solid.

Melting Point: 165-170 ℃

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.28, 2.30 (s and s, total 3H), 2.50, 2.51 (s and s, total 3H), 3.01 (s, 6H), 7.53-7.98 ( m, 8H), 11.38, 11.42 (brs and brs, total 1 H), 12.03, 12.17 (brs and brs, total 1 H).

Example  65

(N-hydroxy-N- methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (65)

(N-hydroxy-N-methyl) -4- (5-benzoylbenzoimidazole-2) by using N-methylhydroxyamine hydrochloride in place of N, N, N'-trimethylethylenediamine according to Example 11 I) -3,5-dimethylpyrrole-2-carboxamide (41%) was obtained as a pale yellow solid.

Melting point: 227-229 ° C. (decomposition).

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.38-2.57 (m, 6H), 3.30 (s, 3H), 7.54-8.00 (m, 8H), 9.92 (s, 1H), 11.19, 11.23 (brs and brs, total 1 H), 12.11, 12.25 (s and s, total 1 H).

Example  66

(N― methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carr Copy Mid (66)

According to Example 11, (N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-by using 40% methylamine aqueous solution instead of N, N, N'-trimethylethylenediamine. Dimethylpyrrole-2-carboxamide (81%) was obtained as a pale yellow solid.

Melting point: 188-190 degreeC.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.41-2.53 (m, 6H), 2.78, 2.79 (s and s, total 3H), 7.33-7.47 (br, 1H), 7.52-7.99 (m , 8H), 11.36, 11.40 (brs and brs, total 1H), 12.11, 12.26 (s and s, total 1H).

Example  67

(N-hydroxy methyl ) -4 (5-) Benzoylbenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (67)

37% in a solution of 4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (358 mg, 1.0 mmol) obtained in Example 12 in dimethyl sulfoxide (3 ml). Formaldehyde aqueous solution (0.17 mL) and 1 N sodium hydroxide aqueous solution (0.02 mL) were added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, and the precipitated solid was filtered, washed with water, and dried under reduced pressure. The resulting crude crystals were purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 15 to 1:10) to thereby give (N-hydroxymethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3. , 5-dimethylpyrrole-2-carboxamide (76%) was obtained as a pale yellow solid.

Melting point: 196-210 degreeC.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.48 (s, 3H), 2.53 (s, 3H), 4.72 (dd, J = 6.6, 6.6 Hz, 2H), 5.59 (t, J = 6.6 Hz, 1H), 7.53-77.7 (m, 7H), 7.91 (s, 1H), 8.03 (t, J = 6.3 Hz, 1H), 11.44 (brs, 1H), 12.10-12.18 (br, 1H).

Example  68

4― (5― Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Ethyl carboxylate  Ester (68)

Sodium bisulfite (0.87 g, 8.4 mmol) and 3,5 in an N, N-acetamide (25 mL) solution of 4-phenoxyl-1,2-phenylenediamine (1.60 g, 8.0 mmol), already known in the literature -Dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester (1.64 g, 8.4 mmol) was added, and it heated at 110 degreeC and stirred for 18 hours. The reaction solution was allowed to cool to room temperature, added with 5% aqueous sodium carbonate solution, extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by filtration off the desiccant and then solvent distillation under reduced pressure was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 100 to 1:30) to give 4- (5-phenoxybenzoimidazole-2). I) -3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (2.27 g, 76%) was obtained as a pale yellow solid.

Melting point: 239-242 ° C.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.39 (t, J = 7.1 Hz, 3H), 2.57 (s, 6H), 4.35 (q, J = 7.1 Hz, 2H), 6.96-7.82 (m, 8H), 8.94 (brs, 1 H), 9.17 (br, 1 H).

Example  69

4― (5― Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxylic acid (69)

4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (1.88 g, 5.0 mmol) obtained in Example 68 was diluted with ethanol (10 mL) and tetrahydrofuran. It dissolved in (5 mL), added 4 N sodium hydroxide aqueous solution (6 mL, 24 mmol), and stirred at 80 degreeC for 6 hours. The obtained reaction solution was cooled to 0 ° C., neutralized with 1 N hydrochloric acid water, and the precipitated solid was filtered, washed with water and dried under reduced pressure to obtain 4- (5-phenoxybenzoimidazol-2-yl) -3,5 -Dimethylpyrrole-2-carboxylic acid (1.70 g, 98%) was obtained as a pale yellow solid.

Melting point: 167-172 degreeC (decomposition).

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.42 (s, 3H), 2.47 (s, 3H), 6.85 -7.16 (m, 5H), 7.30-7.38 (m, 2H), 7.54 (d , J = 8.6 Hz, 1H), 11.44 (brs, 1H), 11.50-12.38 (br, 3H).

Example  70

((4-(5- Phenoxybenzoimidazole -2 -yl) -3,5-dimethylpyrrole-2-yl) -2-carbonyl) Pyrrolidine (70)

N, N-dimethylformamide (3 mL) solution of 4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid (174 mg, 0.5 mmol) obtained in Example 69 1-hydroxybenzotriazole monohydrate (84 mg, 0.55 mmol), 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (115 mg, 0.6 mmol), pyrrolidine (0.06 mL, 0.75 mmol) Was added and stirred for 19 hours at 60 ℃. The obtained reaction liquid was left to cool to room temperature, water and the saturated sodium hydrogencarbonate aqueous solution were added, and the precipitated solid was filtered. The resulting crude crystals were purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 20 to 1:10) to obtain ((4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole). 2-yl) -2-carbonyl) pyrrolidine (116 mg, 58%) was obtained as a pale yellow solid.

Melting point: 251-254 degreeC.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.90 (br, 4H), 2.25 (s, 3H), 2.28 (s, 3H), 3.55 (br, 4H), 6.91-7.72 (m, 8H), 9.44 (s, 1 H), 10.30 (brs, 1 H).

Example  71

((4-(5- Phenoxybenzoimidazole -2-yl) -3,5-dimethylpyrrole-2-yl) -2-carbonyl) morpholine (71)

By using morpholine instead of pyrrolidine according to Example 70 ((4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) -2-carbonyl) A morpholine (67%) was obtained as a pale yellow solid.

Melting point: 268-270 degreeC.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.24 (s, 3H), 2.28 (s, 3H), 3.38 -3.82 (m, 8H), 6.91 -7.12 (m, 4H), 7.21 -7.73 (m , 4H), 9.43 (s, 1H), 10.00 (brs, 1H).

Example  72

N- (2- Pyridyl Ethyl) -4 (5-) Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (72)

N- (2- (2-pyridyl) ethyl) -4- (5-phenoxybenzoimidazol-2-yl) by using 2- (2-aminoethyl) pyridine instead of pyrrolidine according to Example 70 ) -3,5-dimethylpyrrole-2-carboxamide (76%) was obtained as a pale yellow solid.

Melting point: 290-293 degreeC.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.42 (s, 3H), 2.43 (s, 3H), 3.01 (t, J = 7.1 Hz, 2H), 3.64 (dt, J = 12.5, 7.1 Hz, 2H), 6.83-7.84 (m, 12H), 8.43-8.65 (m, 1H), 11.31 (s, 1H), 11.81, 11.92 (s and s, total 1H).

Example  73

N― ( Methoxy ) -4 (5-) Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Ka Leboxamide (73)

N- (methoxy) -4- (5-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole by using O-methylhydroxyamine hydrochloride instead of pyrrolidine according to Example 70 2-carboxamide (71%) was obtained as a pale yellow solid.

Melting point: 166-168 degreeC.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.43 (s, 6H), 3.71 (s, 3H), 6.83 -7.64 (m, 8H), 10.71 (s, 1H), 11.38 (s, 1H), 11.83, 11.94 (s and s, total 1 H).

Example  74

(N― Methoxy ―N― methyl ) -4 (5-) Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide (74)

According to Example 15 (3), (N-methoxy-N-methyl) -4- (5-phenoxy is used by using 4-phenoxy group-1,2-phenylenediamine instead of 3,4-diaminobenzophenone. Cibenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (74%) was obtained as a pale yellow solid.

Melting point: 130-134 degreeC.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.57 (s, 6H), 3.35 (s, 3H), 3.72 (s, 3H), 6.92-7.85 (m, 8H), 9.14-9.43 (br, 2H ).

Example  75

2― (2― Cyano -3,5-dimethylpyrrole-4 -yl) -5 Phenoxybenzoimidazole (75)

According to Example 13 (2), by using 4-phenoxy-1,2-phenylenediamine instead of 3,4-diaminobenzophenone (2- (2-cyano-3,5-dimethylpyrrole-4) -Yl) -5-phenoxybenzoimidazole (77%) was obtained as a pale yellow solid.

Melting point: 278-280 degreeC.

¹ H-NMR (CDCl ₃ ): δ (ppm) 2.42 (s, 3H), 2.48 (s, 3H), 6.90-77.7 (m, 8H), 10.61 (brs, 1H), 11.31 (s, 1H).

Example  76

4― (5― Phenoxybenzoimidazole -2-day) -3,5- Dimethylfuran -2- Carboxamide (76)

4- (5-phenoxybenzoimidazol-2-yl) -3 by using 4-phenoxy group-1,2-phenylenediamine instead of 3,4-diaminobenzophenone according to Example 2 (3) , 5-dimethylfuran-2-carboxamide (59%) was obtained as a pale yellow solid.

Melting point: 248-251 degreeC.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 2.49 (s, 3H), 2.57 (s, 3H), 6.89-7.86 (m, 10H), 12.27 (brs, 1H).

Comparative example  One

4― (5― (4― Pyridylsulphenyl ) -6 Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxylic acid ethyl ester

2.0 g (35.8) of iron in 2.75 g (8.10 mmol) of 4-phenoxy-2-nitro-5 (4-pyridylsulphenyl) aniline synthesized according to the method described in Japanese Patent Application Laid-Open No. 2000-026430. mmol) was added to make a mixture, and 10 mL (10.0 mmol) of 1N ammonium chloride aqueous solution was added, and the mixture was stirred at 85 ° C for 3 hours. Then, the reaction liquid was returned to room temperature, 60 ml of ethyl acetate was added, and the insolubles were filtered off. The obtained filtrate was separated, the ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated after filtration, and dried under reduced pressure after that to obtain a crude diamine (2.0 g).

1.0 g (3.23 mmol) of the obtained crude diamine was dissolved in 15 ml of dimethylacetamide, and 0.37 g (3.55 mmol) of sodium hydrogen sulfite and 0.69 g of 3,5-dimethyl-4-formylpyrrole-2-carboxylic acid ethyl ester 3.53 mmol) was added, and it heated at 130 degreeC and stirred for 16 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, a 5% aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the precipitated solid was filtered, washed with water, and dried under reduced pressure. The resulting crude crystals were purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 50 to 1:10) to thereby give 4- (5- (4-pyridylsulphenyl) -6-phenoxybenzoimidazol-2-yl ) -3,5-dimethylpyrrole-2-carboxylic acid ethyl ester (0.75 g, 48%) was obtained as an amorphous.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.35 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H), 2.55 (s, 3H), 4.29 (q, J = 7.2 Hz) , 7.10-7.80 (m, 9H), 8.23-8.36 (m, 2H), 11.61 (br, 1H), 12.20 (br, 1H).

Comparative example  2

(N, N-dimethyl) -4- (5- (4- Pyridylsulphenyl ) -6 Phenoxybenzoimidazole -2-day) -3,5- dimethylpyrrole-2- Carboxamide

To 0.48 g (1.0 mmol) of 4- (5- (4-pyridylsulphenyl) -6-phenoxybenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid ethyl ester obtained in Comparative Example 1 5 ml of ethanol and 3.5 ml (3.5 mmol) of 1 N sodium hydroxide solution were added, followed by stirring at 60 ° C for 17 hours. After cooling, the reaction solution was concentrated, water was added, and the insolubles were separated by filtration. The filtrate was neutralized with 2N hydrochloric acid water and the precipitated solid was filtered, washed with water and dried under reduced pressure to obtain crude carboxylic acid (0.22 g). 0.2 g (0.4 mmol) of crude carboxylic acid was dissolved in 3 ml of N, N-dimethylformamide, 92 mg (0.5 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, and 0.25% aqueous 40% dimethylamine solution. ML (2.2 mmol) was added and the mixture was stirred at 60 ° C for 18 hours. The reaction solution was allowed to cool to room temperature and the solvent was distilled off under reduced pressure. The obtained residue was purified by medium pressure silica gel flash column chromatography (methanol: chloroform = 1: 100 to 1:10) to obtain (N, N-dimethyl) -4- (5- (4-pyridylsulphenyl) -6-phenoxy). Cibenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide (83 mg, 43%) was obtained as an amorphous.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.44-2.55 (m, 6H), 3.02 (s, 6H), 7.08-7.81 (m, 9H), 8.33-8.47 (m, 2H), 11.56 (br, 1H), 12.18 (br, 1H).

Comparative example  3

Comparative example  3 (1)

2―Puraldehyde-5 Diethylphosphonate

A tetrahydrofuran (30 mL) solution of 2-furaldehyde diethyl acetal (13.6 g, 80 mmol) was cooled to -78 deg. C, and 1.6Mn-butyllithium-hexane solution (50 mL, 80 mmol) was added dropwise to the same temperature. It stirred for 1 hour. Chlorodiethylphosphonate (12.7 ml, 88 mmol) was added dropwise to the obtained reaction solution, and stirred at the same temperature for 30 minutes, and then saturated aqueous ammonium chloride solution was added. The precipitated solid was filtered off, water was added to the residue obtained by distilling off the filtrate under reduced pressure, extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. 80% acetic acid (100 mL) was added to the residue obtained by distilling a solvent off under reduced pressure after filtering a drying agent, and it stirred at 90 degreeC for 4 hours. After cooling the reaction solution to room temperature, water was added to the residue obtained by distilling off the solvent under reduced pressure, extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. . The residue obtained by distilling off the solvent under reduced pressure after filtration of the desiccant was purified by medium pressure silica gel flash column chromatography (ethyl acetate: hexane = 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 1: 5: 1), thereby purifying 2-puraldehyde-5 diethylphospho Nate (1.65 g, 9%) was obtained as a pale yellow oily substance.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.30-1.50 (m, 6H), 4.02-4.35 (m, 4H), 7.18-7.32 (m, 2H), 9.80 (s, 1H).

Comparative example  3 (2)

5― Benzophenone -2-(2 Diethylphosphono ―5― Furanil ) Benzoimidazole

Sodium hydrogen sulfite (0.46 g, 4.4 mmol) was added to the N, N-formamide (10 mL) solution of 3, 4- diamino benzophenone (0.85 g, 4.0 mmol), and it heated to 100 degreeC. N, N-formamide (5 ml) of 2-furaldehyde-5-diethylphosphonate (1.16 g, 5.0 mmol) obtained in Comparative Example 3 (1) was added dropwise and stirred at the same temperature for 3 hours. The obtained reaction liquid was left to cool to room temperature, 5% sodium carbonate aqueous solution was added, extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure after filtration of the drying agent was purified by medium pressure silica gel flash column chromatography (ethyl acetate: chloroform = 1: 5 to 1: 1) to give 5-benzophenone-2- (2-diene). Tilphosphono-5-furanyl) benzoimidazole (1.05 g, 62%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ): δ (ppm) 1.38 (t, J = 7.1 Hz, 6H), 4.13-4.35 (m, 4H), 7.20-8.28 (m, 10H), 10.65-11.38 (br, 1H ).

Comparative example  3 (3)

5― Benzophenone -2-(2 Phosphono ―5― Furanil ) Benzoimidazole Dihydrate

47% hydrobromic acid (6.0 ml) and water (4.0) in 5-benzophenone-2- (2-diethylphosphono-5-furanyl) benzoimidazole (424 mg, 1.0 mmol) obtained in Comparative Example 3 (2). Ml) was added and the mixture was stirred at 100 ° C for 8 hours. The obtained reaction liquid was left to cool to room temperature, and the precipitated solid was filtered by adding water to the residue obtained by distilling off the solvent under reduced pressure, washing with water, and drying under reduced pressure to give 5-benzophenone-2- (2-phosphono) 5-Furanil) benzoimidazole dihydrate (359 mg, 89%) was obtained as a pale yellow solid.

Melting point: 224-229 degreeC.

Anal. Cald. for C ₁₈ H ₁₃ N ₂ O ₅ P + 2H ₂ O: C: 53.47%; H: 4.24%; N: 6.93%. Found: C: 53.74%; H: 4.19%; N: 6.92%.

¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.08-7.17 (m, 1H), 7.31-7.39 (m, 1H), 7.53-7.87 (m, 9H), 7.97 (s, 1H).

Experimental Example  1: hematopoietic enzyme inhibition

Urade, Y. (J. Biol. Chem. 262, 3820-3825 (1987)). That is, reaction liquid (49 microliters); 100 mM Tris-HCl (pH 8.0), 1 mM reduced glutathione, 0.1 mg / ml γ-globulin, human hematopoietic enzyme (proper) and the test compound (final concentration: 0.01-100 μM) were preincubated at 25 ° C. for 5 minutes. In addition, a final concentration of 1% DMSO solution was added to the solvent control group (Control group). The reaction was then initiated by adding 1 μl of [ ¹⁴ C] prostaglandin H2 (final concentration: 10 μM). One minute after the start of the reaction, the reaction was stopped by adding 250 µl of a reaction stopper (-20 ml of diethyl ether / methanol / 1M citric acid (30/4/1)).

50 microliters of the upper layer part (organic solvent phase) after completion | finish of reaction was applied to TLC plate, and it developed for 45 minutes at -20 degreeC (developing agent: diethyl ether / methanol / acetic acid (capacity ratio = 90/2/1)). After drying, the plate was exposed to the imaging plate overnight for 1 hour, and the radiation activity corresponding to prostaglandin D2 was analyzed by an image analyzer (Fuji Film). The percentage (%) of each band of the prostaglandin D2 band was calculated, and the 50% inhibitory concentration (IC 50 value) of the test compound for the hematopoietic enzyme was calculated from the inhibition rate for the Control group prepared in each experiment. The results are shown in Tables 1-3.

Compound number Drug concentration (μM) inhibits hematopoietic enzyme 50% One 0. 796 2 0. 274 3 0. 178 4 0. 278 5 1. 45 6 1. 74 7 0. 588 9 0. 110 10 0. 436 11 0. 269 12 0. 100 13 0. 540 14 0. 355 15 0. 256 16 2. 28 17 0. 124 18 0. 080 19 0. 874 20 0. 871 21 0. 304 22 0. 829 23 0. 223 24 0. 496 25 0. 286 26 0. 149 27 0. 309 28 0. 073 29 0. 053 30 0. 113

Compound number Drug concentration (μM) inhibits hematopoietic enzyme 50% 31 0. 090 32 0. 124 34 0. 072 35 0. 746 36 0. 195 37 0. 213 38 0. 136 39 0. 351 40 0. 592 41 1. 45 42 0. 063 43 0. 791 44 1. 67 45 0. 643 46 0. 758 47 0. 269 48 0. 124 49 0. 649 50 0. 843 52 4. 80 53 3. 08 56 4. 78 57 4. 13 58 2. 37 59 3. 56 60 4. 36 62 2. 43 63 1. 25

Compound number Drug concentration (μM) inhibits hematopoietic enzyme 50% 64 0. 377 65 0. 124 66 0. 077 67 0. 109 68 0. 210 69 0. 491 70 0. 614 71 0.870 72 0. 209 73 0. 240 74 0. 263 75 0. 218 76 0. 109 HQL―79 24. 4 Comparative Example 1 〉 30μM Comparative Example 2 〉 30μM Comparative Example 3 29. 3

From the above result, it became clear that the compound of the present invention has a hematopoietic enzyme inhibitory activity superior to HQL-79 known as a hematopoietic enzyme inhibitor.

Experimental Example  2: Rat  Alveolar lavage fluid Prostaglandins D2 Birth  Inhibitory effect

A 7-week-old male Brawn Norway rat was injected subcutaneously with 1 ml / body of a physiological saline solution containing 1 mg of Ovalbumin and 4 mg of alum, and intraperitoneally with 0.06 mg of pertussis toxin bacterium. Dosing was active sensirization. After 14 days of sensitization, 2% ovalbumin was inhaled for 10 minutes, and the alveolar lavage fluid was recovered 1 hour after inhalation. The amount of PGD2 in the alveolar lavage fluid was measured using an EIA kit. The test compound (10 mg / kg) was orally administered 2 hours before antigen inhalation. The results are shown in Table 4.

compound % Inhibition of PGD2 content in alveolar lavage fluid 3 36 13 48 15 〉 72 40 65 42 88

From the above results, it became clear that the compound of the present invention strongly inhibited the amount of PGD2 in the alveolar lavage fluid by oral administration of 10 mg / kg.

Experimental Example  3: Mormot  Antigen-induced Secret  Improvement

Active sensitization was performed by subcutaneous subcutaneous injection of 1 ml / body of 1 mg / ml Ovalbumin physiological saline solution into 5-week-old male Std: Hartley type mormot. After 1 week and 2 weeks after the first sensitization, 10 mg / ml Ovalbumin physiological saline solution was administered in each of the two nasal sinuses by nasal micropipette (nasal sensitization). Three weeks after the first sensitization, a 20 mg / ml Ovalbumin physiological saline solution was administered in a 10 μL intranasal nasal cavity using a micropipette to cause a rhinitis reaction.

Nasal resistance of 100 breaths each, once every 2, 3, 4, 5, 6 and 7 hours before or after Ovalbumin using a comprehensive respiratory function measurement system (Pulmos-I, MIPS) airway resistance, nRaw) was measured, and the average value was made nRaw in each measurement time. The calculation formula which calculates the increase rate of nPaw is shown below.

The increase rate (%) of nRaw of each measurement time =

(NRaw of each measurement time-nRaw before induction) ÷ nRaw * 100 before induction

Evaluation of bipye was conducted by calculating the area under the curve (AUC _{3 -7 hr)} of the rate of increase in nRaw induced after 3-7 hours. In addition, I _{3 ~7 hr} represents the rate of increase in nRaw induced after 3-7 hours.

_{AUC 3 -7 hr = 1/2} (I 3hr + 2 × Ⅰ 4 hr + 2 × Ⅰ 5 hr + 2 × Ⅰ 6 hr + I 7hr)

Compound 15 was selected as a representative compound to confirm the non-lung effect by inhibition of PGD2 production, and was orally administered once daily for 15 days from nasal sensitization after the first sensitization to 3 days after the first sensitization. In addition, the nasal sensitization days (one week and two weeks after the first sensitization) and the induction day were orally administered 1 hour prior to the administration of Ovalbumin nasal.

As a positive control substance, Franlukast, a leukotriene antagonist with strong anti-lung effect, and Ramatroban, a thromboxane antagonist, were used. The results are shown in Table 5 below.

compound Dose (mg / kg) AUC _{3 -7hr} (% and hr) % Inhibition Normal ― 27.0 ± 15.9 ― Control ― 564.8 ± 103.4 ^** 0 15 3 237.9 ± 69.1 ^＃＃ 60.8 10 153.5 ± 27.1 ^＃＃ 76.5 30 65.7 ± 28.9 ^＃＃ 92.8 Franlukast 30 126.3 ± 41.7 ^$$ 81.5 Ramat Lovan 30 183.4 ± 29.3 ^$$ 70.9

3, 10, repeated oral administration of 30㎎ / ㎏ of compound 15 is bipye induced in antigen (increase in nasal resistance: _{3 -7h} AUC) inhibition in a dose-dependent manner, and the inhibition rate was respectively 60.8%, 76.5%, 92.8 %. The non-lung improvement effect of 10 mg / kg of Compound 15 was comparable to the effect of 30 mg / kg administration of franlukast or lamatrobane, and at 30 mg / kg of the same dose, it showed a stronger improvement effect than these positive control substances. .

Examples of the preparation containing the compound of the present invention as an active ingredient are given below.

Formulation example  1 tablet

50 mg of the compound of Example 15

Corn Starch 50mg

50 mg of microcrystalline cellulose

15 mg of hydroxypropyl cellulose

Lactose 47mg

Talc 2mg

Magnesium Stearate 2mg

Ethyl Cellulose 30mg

Unsaturated Glyceride 2mg

Titanium Dioxide 2mg

250 mg of tablets per tablet were prepared according to the conventional method at the said compounding ratio.

Formulation example  2 granules

300 mg of the compound of Example 19

Lactose 540 mg

Corn Starch 100mg

Hydroxypropyl Cellulose 50mg

Talc 10mg

1000 mg of granules per packet were prepared according to the conventional method at the said compounding ratio.

Formulation example  3 Capsule

100 mg of the compound of Example 20

Lactose 30mg

Corn Starch 50mg

10 mg of microcrystalline cellulose

Magnesium Stearate 3mg

According to the conventional method, 193 mg of capsules per capsule were prepared by the said compounding ratio.

Formulation example  4 Injection

100 mg of the compound of Example 21

Sodium chloride 3.5mg

Suitable amount of distilled water for injection

(2 ml per ampoule)

Injection was prepared according to the conventional method at the said compounding ratio.

Formulation example  5 syrups

200 mg of the compound of Example 27

60 g of purified white sugar

5 mg of ethyl parahydroxybenzoate

5 mg of parahydroxy benzoate

Spices

Coloring amount

Purified water

The syrup was prepared according to the conventional method at the said compounding ratio.

Formulation example  6 Suppository

300 mg of the compound of Example 35

Utopezol W-35 1400 mg mg registered trademark, mono-, di- and tri-glyceride mixtures of saturated fatty acids from lauric acid to stearic acid, manufactured by Dynamite Nobel Corporation)

A suppository was prepared according to the conventional method at the said compounding ratio.

According to the present invention there is provided a benzoimidazole compound represented by formula (I) or a salt thereof useful as a prostaglandin D synthetase inhibitor.

The benzimidazole compound or salt thereof of the present invention has excellent prostaglandin D synthetase inhibitory activity.

Therefore, the corresponding benzimidazole compounds of the present invention or salts thereof are based on their excellent prostaglandin D synthetase inhibitory activity, and thus preventive and / or therapeutic agents for diseases involving prostaglandin D2 or its metabolites, such as allergic diseases or inflammatory diseases, It is useful as an inhibitor of deterioration of Alzheimer's disease and brain damage, and other useful effects can be expected.

Claims (18)

Formula (I) [Formula I]

[Wherein, X ¹ represents an oxygen atom or a carbonyl group, and R ¹ represents a furan ring having 1 to 3 substituents or a pyrrole ring which may have 1 to 3 substituents. However, the compound represented by the formula (I) wherein the substituent is a phosphoric acid group or a phosphate ester group is excluded.] The benzimidazole compound or its salt represented by these. The method of claim 1, X ¹ represents a carbonyl group Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents an oxygen atom or a carbonyl group, R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents, The substituent on the pyrrole ring or the furan ring may be a halogen atom, a cyano group, a nitro group, a C1-C6 alkyl group which may have a substituent, a C3-C7 cycloalkyl group which may have a substituent, or a C2 which may have a substituent. is selected from (C = O) -R ² group the group consisting of, - an alkenyl group of to 6 and R ² is a hydrogen atom, a hydroxy group, a substituent which may have an alkyl group of 1 to 6 carbon atoms good represents an alkoxy group or -NR ³ R ⁴ group having 1 to 6 carbon atoms of a good, R <^3> and R <^4> is the same or different, and each has a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group which may have a substituent, a C1-C6 alkoxy group, an amino group, and a substituent which may have a substituent A mono or di (C 1 -C 6 alkyl) amino group which may be present, an aryl group having 6 to 14 carbon atoms which may have a substituent, or a saturated or unsaturated heterocyclic group which may have a substituent, or R ³ and R ⁴ together with adjacent nitrogen atoms in the ring structure, in addition to the adjacent nitrogen atoms in addition to the saturation may have one or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms; An unsaturated cyclic amino group may be formed and the said cyclic amino group may have a substituent. Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents a carbonyl group, R <^1> represents the furan ring which has 1-3 substituents, or the pyrrole ring which may have 1-3 substituents, The substituent on the pyrrole ring or furan ring may have 1 to 3 groups selected from the group consisting of a halogen atom, a cyano group, a nitro group, a halogen atom as a substituent, a hydroxy group and a -NR ^{3 '} R ^{4 '} group. An alkenyl group having 2 to 6 carbon atoms which may have 1 to 3 groups selected from the group consisting of a cyano group, a carboxyl group and a (C1-C6 alkoxy) carbonyl group as the alkyl group of 6 to 6 or a substituent, or-(C = O) -R ² , R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a —NR ³ R ⁴ group, R ^{3 ′} and R ^{4 ′} are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R ^{3 ′} and R ^{4 ′} may have one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms in addition to the adjacent nitrogen atoms in the ring structure together with the adjacent nitrogen atoms. A saturated or unsaturated cyclic amino group may be formed, R ³ And R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other one having a hydrogen atom, a hydroxy group or a substituent having 1 to 6 carbon atoms and optionally having a substituent group having 1 to 6 carbon atoms. Mono or di (C1-C6 alkyl) amino group which may have an alkoxy group, an amino group, a substituent, a C6-C14 aryl group which may have a substituent, or the monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent Or R ³ And R ⁴ together with the adjacent nitrogen atom form a saturated or unsaturated cyclic amino group which may have one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to the adjacent nitrogen atom in the ring structure. The cyclic amino group may be a substituent, and may include a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, a carboxy group, an alkyl group having 1 to 6 carbon atoms which may have a substituent, and a carbon number of 6 to 14 which may have a substituent. May have 1 to 3 groups selected from the group consisting of an aryl group and a (C 1 -C 6 alkoxy) carbonyl group which may have a substituent and a mono or di (C 1 -C 6 alkyl) aminocarbonyl group which may have a substituent. Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents a carbonyl group, R ¹ is a furan ring having ¹ to 3 substituents, or a pyrrole ring having ¹ to 3 substituents with a hydrogen atom bonded to a nitrogen atom, The substituent group bonded to the pyrrole ring and the furan ring may have a group selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a substituent selected from the group consisting of a halogen atom, a hydroxy group, a dimethylamino group and a pyrrolidinyl group. as the alkyl group, the substituent of 6 cyano group, a carboxyl group and (C1-C6 alkoxy group) which may have one 1 is selected from the group consisting of a carbonyl group and good ethenyl group - is selected from (C = O) -R ² group consisting of, R ² represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or —NR ³ R ⁴ , One of R ³ and R ⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 3 carbon atoms which may have a substituent, or having 1 to 3 carbon atoms. Selected from the group consisting of an alkoxy group, a phenyl group which may have a substituent, or a morpholino group, an isoxazolyl group, an indolyl group, a methylenedioxyphenyl group, an ethylenedioxyphenyl group, a dihydrobenzofuranyl group and a benzothiazolyl group Heterocyclic group-The heterocyclic group may have a substituent-or, R ³ and R ⁴ together with adjacent nitrogen atoms may form a saturated or unsaturated cyclic amino group which may have one hetero atom selected from a nitrogen atom and an oxygen atom in addition to the adjacent nitrogen atom in the ring structure; Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents a carbonyl group, R ¹ is a furan ring having two or three substituents, or a pyrrole ring having two or three substituents together with a hydrogen atom bonded to a nitrogen atom, wherein the two furan rings and the pyrrole ring constituting the pyrrole ring The substituent on the carbon atom is an alkyl group having 1 to 6 carbon atoms, a hydrogen atom is bonded to one remaining carbon atom, or a cyano group or a — (C═O) —R ² group is bonded as a substituent. R ² represents a hydroxy group, an alkoxy group having 1 to 3 carbon atoms, or a —NR ³ R ⁴ group, R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Phenyl group, morpholino group, isoxazolyl group, indolyl group, methylenedioxy which may have 1 to 3 groups selected from the group consisting of a halogen group, a cyano group and a C1-6 alkoxy group as the alkoxy group of 3 A phenyl group, ethylenedioxyphenyl group, dihydrobenzofuranyl group, or benzothiazolyl group, or —NR ³ R ⁴ group represents a pyrrolidinyl group, thiazolidinyl group, pyrazolinyl group, morpholino group, or piperazinyl group Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents a carbonyl group, R ¹ is a furan ring having three substituents and bonded to a benzoimidazole ring at the 4-position, or having 3 substituents together with a hydrogen atom bonded to a nitrogen atom, and bonded to a benzoimidazole ring at the 4-position Represents a pyrrole ring, In the substituents on the furan ring and the pyrrole ring, the 3- and 5-position substituents are alkyl groups having 1 to 3 carbon atoms, the 2-position substituent represents a cyano group or a-(C = O) -R ² group, R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group, R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other is a C1-C3 alkyl group which may have a hydrogen atom, a hydroxyl group, a substituent, and C1-C3 may have a substituent. Or a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a cyano group and a C1 to C3 alkoxy group as the alkoxy group of 3 or a substituent, or -NR ³ R ⁴ group represents a pyrrolidinyl group, a pyrazolinyl group, or a morpholino group Benzimidazole compounds or salts thereof. The method of claim 1, X ¹ represents a carbonyl group, R ¹ represents a pyrrole ring having three substituents and a bond to a benzoimidazole ring at the 4-position together with a hydrogen atom bonded to a nitrogen atom, Among the substituents on the pyrrole ring, the substituents at the 3-position and 5-position represent a methyl group, and the 2-position substituent represents a-(C = O) -R ² group, R ² represents a hydroxy group, an ethoxy group, or a —NR ³ R ⁴ group, R <^3> and R <^4> is a hydrogen atom or a C1-C3 alkyl group, and the other represents a C1-C3 alkyl group or a C1-C3 alkoxy group which may have a substituent, or -NR ³ R ⁴ group represents a pyrrolidinyl group or a morpholino group Benzimidazole compounds or salts thereof. The method of claim 1, (4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethyl-2-furanylcarbonyl) pyrrolidine, 4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxylic acid, 2- (2-cyano-3,5-dimethyl-pyrrole-4-yl) -5-benzoylbenzoimidazole, N- (methoxy) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide, (N-methoxy-N-methyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide, N- (3-dimethylaminopropyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide, N- (2- (2-pyridyl) ethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide, ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) morpholine, ((4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-yl) carbonyl) pyrazoline, or (N, N-dimethyl) -4- (5-benzoylbenzoimidazol-2-yl) -3,5-dimethylpyrrole-2-carboxamide Benzimidazole compounds or salts thereof. An effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Pharmaceutical composition. An effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier Prostaglandin D synthase inhibitors. An effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. An agent for preventing and / or treating a disease involving prostaglandin D2 or a metabolite thereof. The method of claim 12, The disease involving prostaglandin D2 or its metabolites may be allergic, inflammatory, Alzheimer's, or brain damage. Prophylactic and / or therapeutic agents. A prophylactic and / or therapeutic agent for allergic diseases, comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. An agent for preventing and / or treating an inflammatory disease, comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. An agent for preventing and / or treating Alzheimer's disease or brain injury, comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method for preventing or treating a disease involving prostaglandin D2 or a metabolite thereof, comprising administering to a patient an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for preparing a prostaglandin D synthetase inhibitor.